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Improving patient safety during facial filler treatments in aesthetic medicine

van Loghem, J.A.J.

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2020
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van Loghem, J. A. J. (2020). Improving patient safety during facial filler treatments in
aesthetic medicine. [Thesis, fully internal, Universiteit van Amsterdam].

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 Improving patient safety
during facial filler treatments
in aesthetic medicine

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor

aan de Universiteit van Amsterdam
op gezag van de Rector Magnificus
prof. dr. ir. K.I.J. Maex

ten overstaan van een door het College voor Promoties ingestelde commissie,
in het openbaar te verdedigen in de Agnietenkapel
op woensdag 28 oktober 2020, te 13:00 uur

door Jani Adriaan Joghem van Loghem

geboren te Amsterdam

©️ Jani van Loghem, Amsterdam 2020.

All rights reserved. No part of this book may be reproduced, stored in a retrieval system,
or transmitted in any form or by any means, electronic, mechanical, photocopying
or otherwise, without the prior permission of the holder of the copyright.

Author: Jani A.J. van Loghem, MSc

Concept: Rosa Koolhoven
Design: Eszter Takács
Printed by: Buijten & Schipperheijn, Amsterdam

Publication of this thesis was financially supported by Merz Aesthetics and UMA Institute.

www.uma-institute.com
promotiecommissie
Promotor:
Prof. dr. R.O. Schlingemann AMC – UvA

Copromotor:
Dr. P. Saeed AMC – UvA

Overige leden:
Prof. Dr. Med. M. Kerscher University of Hamburg, Germany
Prof. Dr. M.I. van Berge Henegouwen AMC – UvA
Prof. Dr. Y. A. Yutskovskaya Vladivostok State Medical University, Russia
Dr. O. Lapid AMC – UvA
Dr. S.S. Gisbertz AMC – UvA

Faculteit der geneeskunde

 This is for my grandparents. More than a century ago, Edgar Allan Poe
understood the ability of facial expressions to guide lives:
Thank you for being such an inspiration to me.
When I wish to find out
how wise or how stupid or
how good or how wicked is
anyone, or what are his thoughts
at the moment, I fashion the
expression of my face, as
accurately as possible, in
accordance with the
expression of his, and then
wait to see what thoughts
or sentiments arise in my
mind or heart, as if to match
or correspond with
Prof. Dr. J. J. van Loghem and Dr. P.E. van Loghem-Langereis the expression.

8 chapter 1 9
 table of content

01 General introduction
p.10
02 Calcium hydroxylapatite:
over a decade of clinical
experience
07
Combined aesthetic interventions for
prevention of facial aging, and restoration
and beautification of face and body.

03 08 09
p.20 p.116

Cannula Versus Sharp Needle Complication Management Managing Intravascular

for Placement of Soft Tissue following Rejuvenation Procedures Complications Following Treatment
Fillers: An Observational with Hyaluronic Acid Fillers – an with Calcium Hydroxylapatite: An

04 05 10
Cadaver Study Algorithm-based Approach. Expert Consensus.
p.40 p.130 p.150

Sensitivity of aspiration as a Use of calcium hydroxylapatite Consensus on the use of

safety test before injection of in the upper third of the face: fillers from the Belotero
soft tissue fillers Retrospective analysis of techniques, CPM range: best practice in
p.70 dilutions and adverse events specific facial indications

06 gd ap
p.86 p.174

Left/Right Pain Asymmetry General

With Injectable Cosmetic Discussion Appendices / 230
Treatments for the Face. p.220 Nederlandstalige Samenvatting / p.232
p.100 English Summary / p.234
General protocol for a Global Facial
Approach / p.236
Crash kit for filler complications / p.238
List of publications, co-authors
and their contributions / p.240
Curriculum Vitae / p.241
Portfolio / p.244
Acknowledgements / p.246

10 chapter 1 11
 01
General Introduction

12 chapter 1 13
 aesthetic medicine
In The Netherlands, aesthetic medicine is the most recent specialty to be recognized as a separate field of medicine, Soft tissue filler products
gaining official status on July 1st, 2019, and making The Netherlands only the second country in the world after
Colombia to officially recognize this medical field and institute an official educational postgraduate medical specialty In a market where patients are less willing to undergo considerable downtime and do not want a major surgical
program for physicians in training1. procedure, the demand for soft tissue fillers is increasing. According to data from the Dutch Society of Aesthetic
Medicine (NVCG), hyaluronic acid (HA) and calcium hydroxylapatite (CaHA) filler treatments are the second and third
According to the World Health Organization (WHO), health is defined as a state of complete physical, mental and most popular nonsurgical injectable procedures performed in The Netherlands after botulinum toxin injections; the
social well-being2. Aesthetic medicine can have an impact on all aspects of this definition. Physical health is latter procedure is frequently performed in concert with soft tissue filler injections and it seems logical that botulinum
maintained and improved by treating aging and damaged skin, sometimes even removing (pre)malignant cells, thereby toxin is injected more frequently as the duration of effect is significantly shorter (3-4 months) versus the duration of
promoting healthy skin that increases attractiveness3. Mental health is improved by facial feedback, whereby an filler treatments (4-18 months).10
attractive, youthful look is reflected in the mental state of the individual4. Finally, social health is improved in
individuals that feel more beautiful and attractive by improving confidence levels and quality of life5. Therefore even At the forefront of developments in aesthetic medicine, physicians have advanced beyond filling wrinkles and are now
though the procedures performed by an aesthetic physician are focused on an individual’s external appearance, targeting specific facial sites for deep volumetric augmentation of bone and deep fat, as well as retaining ligaments,
improving an individual’s psychological well-being is also an important goal of treatment. subcutaneous fibrous septae, and subcutaneous fat. As aging is a multilevel process, treatment options for natural
results should include reconstruction of a youthful anatomy, targeting all anatomical layers in all facial areas. This
Over the last few decades, the field of aesthetic medicine has been steadily growing in complexity and technical range of indications requires varied solutions. Over the last few decades, a multitude of "dermal" fillers have entered
ability. From invasive, open surgical procedures with hospitalization and weeks of downtime, we have seen a shift the market that are injected not only in the dermis, but also in many other anatomical layers from the skin to the
toward more minimally-invasive surgical procedures as well as nonsurgical procedures. Injectable fillers have evolved periosteum.8 Depending on the intended effect, a filler product should have specific rheological characteristics. For
from short-acting, animal-based or permanent (non-degradable), plastic-like products to highly biocompatible, example, when injected into the superficial skin, a gel should be soft and cohesive to allow even integration into the
biodegradable, non-allergenic fillers with a range of tailor-made rheological properties and longevities with very low intercellular matrix and avoid visible and palpable lumps. Such a gel is also required to avoid the Tyndall effect which
risk of late inflammatory reactions.6,7 The manner in which soft tissue fillers are used has also evolved from an initial occurs when depositions of a clear gel act as an optic chamber, absorbing the longer, red light wavelengths and
focus on filling lines and wrinkles to a more global approach that includes volumetric augmentation for reconstruction reflecting the shorter, blue wavelengths, resulting in a bluish discoloration at the site of injected product.11 When there
of youthful anatomy and correction of excess volume loss. At the same time, innovative methods have been is significant skin laxity, a product should be selected that has biostimulatory properties to induce neocollagenesis
developed to treat indications beyond the face.8 Neurotoxins (botulinum toxin type A) have advanced from products and reinforce the skin. It should stimulate fibroblasts to actively produce collagen, elastin and hyaluronic acid, and
containing high doses of bacterial proteins that were linked to tolerance, neutralizing antibodies and treatment induce fibroblast mitosis and differentiation into myofibroblasts for a tightening and lifting effect.8 When injected into
immunity, to new generations of botulinum toxin formulations with very low quantities of unnecessary bacterial the superficial fat, the product should behave like fat, feel like fat, and not interfere with the stresses of muscular
proteins.9 There is now even a neurotoxin product on the market that only contains the pharmacologically active activity. A beautiful result will be a natural result, where the patients looks great, but not injected. If the deep fat
botulinum toxin protein and thus has very low immunogenic potential.10 Lasers have been on the aesthetic market for requires volumizing, the product should be able to do just that, without being palpable or otherwise obvious. In
decades and have advanced from fully ablative to fractionated devices. With the latter, only a fraction of the skin is contrast, when the face needs to be lifted by pushing up the retaining ligaments, the chosen product should be stiff
treated, the layers in between remain intact and can repopulate the damaged skin, significantly decreasing recovery and strong, with high viscosity and elasticity. In this case it is acceptable if the product is palpable, as its role is to act
time. Other energy-based devices that have come to the market comprise a multitude of lasers with different like bone or tendinous structures.
wavelengths and pulse durations, micro-focused ultrasound (MFU) devices, acoustic wave energy, plasma energy,
LED light, intense-pulsed light (ILP), radiofrequency (RF), cryotherapy, and carboxytherapy, to name a few. Minimally- All in all, very precise product characteristics are necessary for the intended effect. Other requirements include a
invasive procedures such as barbed threads (surgical suture material with cones or hooks) for nonsurgical face lifts, product that is degradable with a longevity that avoids too frequent repeat visits, that does not induce immunologic
and technological advancements such as the development of the blunt-tipped injection cannula have also made reactions, is biocompatible, and if possible, that has a reversing agent so that the injected product can be dissolved
irreversible changes to aesthetic medical practices around the world. within minutes or hours, for example in the case of inadvertent intravascular injection.

The field of aesthetic medicine is in a state of constant flux and new technological developments, fueled by the This demanding list of product characteristics is difficult to achieve even among market leaders in the aesthetic field.
innovative minds of practitioners as well as pharmaceutical companies, who are eager to contribute to this young and For example, an HA filler family was introduced to the market without proper long-term follow-up and clinical
growing medical discipline. The field has now become so complex and the treatment possibilities so diverse that it investigation and was subsequently found to induce late inflammatory reactions in up to 1% of treated patients.12
can no longer be viewed as just a subdivision of existing specialties such as ophthalmology, plastic surgery or Another example is the hyper-crosslinked Hyacorp HA filler, a particle-based product that has induced foreign body
dermatology. The Netherlands is the first country in Europe to introduce Aesthetic Medicine as an official medical reactions including recurrent swelling, redness and even sterile abscesses in a multitude of patients and appears
profile specialty and where physicians can follow a formal, 2-year, full-time, post-graduate training program in resistant to enzymatic degradation by hyaluronidase.13 The responsibility for the clinical safety of injectable fillers lies
Aesthetic Medicine, which will provide them with the protected title Aesthetic Physician, KNMG (in Dutch: on the shoulders of the manufacturers and should be vigorously checked by governmental bodies before allowing
Cosmetisch Arts, KNMG). On completion of the training, the aesthetic physician will be proficient in the use of entry to the market. The American Food and Drug Administration (FDA) requires a significant amount of clinical safety
injectables including botulinum toxin type A and soft tissue fillers, lasers and other energy-based devices, skin quality data before any product can enter the US market. Fortunately, in the EU, the CE mark has recently been updated to
improvement with topicals, chemical peels, as well as other modalities, and will have sufficient theoretical knowledge include more long-term clinical studies and current products in the category of Class IV Medical devices can no
of aesthetic surgery to advise patients in that direction. longer extrapolate clinical research data from previous products, but have to submit long-term follow-up with the
product for which the CE mark is being applied for. Even though the CE mark of today provides a reasonable safety
certificate, the injecting physician also holds responsibility for the safety of the chosen product for treatment of his or
her patients.

14 chapter 1 15
 aesthetic medicine
Radiesse (Merz Aesthetics, Raleigh, NC, USA), which is a biphasic injectable soft tissue filler consisting of CaHA Table 1
microspheres of 25-45 micrometers in diameter, suspended in a carboxymethylcellulose (CMC) gel carrier. This Product characteristics linked to intended effect.
product is referred to as CaHA in the medical literature, as this is the active ingredient that stimulates neocollagenesis
by fibroblast activation. Both sponsored and independent studies confirm that CaHA is one of the safest products on
the market in terms of product-related complications.8 In addition to CaHA, HA products, the gold standard of soft Intended effects Product characteristics
tissue fillers will be discussed, how these products can be injected in the face in the safest way and how possible
complications can be managed.14 Skin quality improvement Hydration, elastin, collagen production, skin tone, glow

Filling fine wrinkles Cohesive, low visco-elasticity

Soft tissue filler related anatomy
Filling deep wrinkles Elastic, cohesive, skin quality improvement
Evidence for significant age-related, volume loss in specific deep fat compartments and facial bone resorption is well
documented in the medical literature. The aging process occurs in all anatomical layers of the face and rejuvenation Lifting (ligaments) Elastic, cohesive
should therefore not be limited to dermal signs of aging. Injection of fillers at strategic target sites can reconstruct a
youthful anatomy and thereby provide the patient with a natural result.15,16 As the relatively new field of aesthetic Projecting Elastic, volumizing
medicine develops, practitioners are using filler products and techniques in an increasing number of facial and
non-facial areas with reduced complications and increased patient satisfaction. To provide natural-looking results, the Volumizing Volumizing, respect facial mimics
physician must have a thorough knowledge of the anatomical changes taking place during the aging process and be
able to place fillers in the specific areas of volume loss. Contouring, shaping, sharpness Elastic, low water retention

Aesthetic results are the primary goal for the aesthetic patient who wants natural-looking results with minimal down-
time. The aesthetic physician must therefore not only possess a profound knowledge of the anatomical danger zones,
but also detailed knowledge of age-related anatomical changes and how to recognize these changes during facial Soft tissue filler related complications
assessment. In addition, knowledge of optimal facial proportions, gender and racial differences, as well as cultural
ideals of beauty and attractiveness are all necessary for the aesthetic physician and must be combined with good The aesthetic patient is generally healthy and attending a physician’s practice for aesthetic needs and not to cure an
communication and consultation skills. After determining exactly what the patient requires, the aesthetic physician illness. The aesthetic physician must therefore optimize the chances that no harm will be done to the patient, and
should have a detailed knowledge of the products at his disposal to achieve the desired results. Rheological properties complication risks of ≥1% are seen as unacceptable. Even though filler treatments are generally very safe,
such as cohesivity, elasticity and viscosity narrow the range of filler products to specific indications (figure 1, table 1). complications, when they occur, can be severe and devastating to an individual. A number of types of complication
can occur with soft tissue fillers, but preventative measures can be taken to significantly reduce the risk of their
occurrence (Table 2).

Volumizing / Projecting

Projecting, lifting Smoothing, relaxing

Volumizing
Lifting
Smoothing
Projecting, lifting
Sharpness, contouring
Volumizing

Skin quality Shaping, contouring

Contouring
Projecting, contouring

Figure 1
Highlights and shadows in the face linked to specific goals of soft tissue fillers

16 chapter 1 17
 aesthetic medicine
Table 2
Complications and adverse events and their preventative measures A

Complications and Prevention

adverse events

Pain on injection Local anesthesia, starting on the left side

Ecchymosis and Cold packs, adrenalized lidocaine, use of blunt cannulas. Beware of patients
hematomas on anticoagulants, and perform immediate compression when visible bleeding
is seen

Neovascularization Place fillers only subcutaneously (not in the skin), beware of patients
with rosacea

Hyperpigmentation Beware of patients with Fitzpatrick skin types V / VI, and of sun exposure after bruising/hematoma

Tyndall effect Select the correct filler, avoid superficial filler placement

B
Postinterventional Split treatment over multiple visits, beware of patients with rosacea who have increased risk of erythema
edema and edema after treatment.

Malar edema No superficial injections in the area of the malar septum, beware of personal or family history
of malar edema.

Allergic reaction Beware of patients with history of allergic reactions, consider performing
a skin test

Non-inflammatory Proper injection technique, product choice and selection of target area,
nodules avoid overcorrection

Inflammatory nodules Provide an aseptic working environment, avoid products with higher risk of granuloma formation

Infection Provide an aseptic working environment, use only high quality products
(prophylactic antibiotics/antivirals)

Vascular compromise Use blunt cannulas (25G or thicker) and small boluses in high-risk areas, slow injection, long aspiration
(necrosis, blindness) (needle), manual compression of arteries. Beware of post-surgical patients (scars).

Migration of filler Proper product selection

Figure 2
Many of these adverse events are self-limiting, not very dangerous and/or easy to resolve. The most severe Soft tissue filler complications
complications are inflammatory nodules (that may lead to granuloma formation), necrosis and blindness. Foreign body Figure 2A: Example of a product-related complication (late inflammatory reaction syndrome, LIRS,
granuloma is a typical product-related, late inflammatory complication (figure 2A), while necrosis and blindness are a discussed in Chapter 8) after hyaluronic acid filler (Hyacorp) injection. From left to right: before - active
result of inadvertent intravascular injection and are technique related (figure 2B). To reduce the risk of the latter, phase initial presentation - active phase edema, a few days after initial presentation (recurring every 3-4
attention should be paid to choice of instrument (e.g. blunt cannula) and specific injection techniques, such as weeks). Images from UMA Institute.
choosing the anatomical layer with the lowest risk and performing injections with the blunt cannula perpendicular to Figure 2B: Example of a technique-related complication (intra-arterial embolization with extensive
the direction of the arteries. In this thesis, I will describe numerous preventative measures that can be taken to necrosis) after injection of hyaluronic acid. Image from Funt D, Pavicic T. Dermal fillers in aesthetics: an
optimize patient safety and minimize complication risk including: product selection, instrument selection, technique overview of adverse events and treatment approaches. Clin Cosmet Investig Dermatol. 2013;6:295–316.
selection as well as additional preventative measures. Original publisher: Dove Medical Press

18 chapter 1 19
 scope of the thesis references
To further define and develop this exciting new medical field, both in terms of best clinical practice and scientific 1. Besluit Cosmetische Geneeskunde: https://www.knmg. with a botulinumtoxin type A preparation free of
research, a very basic question must be answered about one of the most popular and potentially dangerous treatment nl/opleiding-herregistratie-carriere/cgs/regelgeving/ complexing proteins--a single cohort 4-year follow-
options: how can we optimize safety when injecting soft tissue fillers in the face? cosmetische-geneeskunde.htm up study.. BMJ Open 2012;0:e000646. doi:10.1136/
To answer this question, it is necessary to look at the properties of the injected products, the instruments used for 2. https://www.who.int/about/who-we-are/constitution bmjopen-2011-000646
injection, the techniques of injection, the amount of filler material that is injected, the anatomical layer of filler 3. Fabi SG, Burgess C, Carruthers A, et al. Consensus 10. Data on file at the Dutch Society of Aesthetic Medicine;
injection, and additional safety measures such as the availability of a crash kit for use in case of complications. recommendations for combined aesthetic interventions [email protected]
using botulinum toxin, fillers, and microfocused 11. Micheels P, Sarazin D, Besse S, Sundaram H, Flynn
In Chapter 2, we describe the history and evolution of a biostimulatory filler product, CaHA, commercially marketed ultrasound in the neck, décolletage, hands, and other TC. A blanching technique for intradermal injection
under the name Radiesse. The outstanding safety profile of this product is reviewed as well as a decade of clinical areas of the body. Dermatol Surg. 2016;42(10):1199– of the hyaluronic acid belotero. Plast Reconstr Surg.
experience by the author. The use of CaHA in several facial areas is discussed in relation to their anatomy, age-related 1208. 2013;132:59S.
anatomical changes, as well as specific arterial danger zones. Technical suggestions are proposed in terms of a global 4. Alam M, Barrett KC, Hodapp RM, Arndt KA. Botulinum 12. Sadeghpour M, Quatrano NA, Bonati LM, Arndt KA,
facial injection protocol to reverse the signs of aging and create a natural-looking facial appearance. toxin and the facial feedback hypothesis: can looking Dover JS, Kaminer MS. Delayed-Onset Nodules to
better make you feel happier? J Am Acad Dermatol. 2008 Differentially Crosslinked Hyaluronic Acids: Comparative
In Chapter 3, we present the results from an experimental observational cadaver study in which we compared Jun;58(6):1061-72. doi: 10.1016/j.jaad.2007.10.649. Incidence and Risk Assessment. Dermatol Surg. 2019 Feb
instruments commonly used to perform soft tissue filler treatments: sharp needles and blunt-tipped cannulas. As facial 5. Dayan SH. What is beauty, and why do we care so much 14. doi: 10.1097/DSS.0000000000001814.
rejuvenation procedures are commonly performed with fillers placed in the deep fat or on the periosteum, we also about it? Arch Facial Plast Surg. 2011 Jan-Feb;13(1):66-7. 13. https://www.rivm.nl/bibliotheek/rapporten/2017-0023.
compared needles to cannulas for several periosteal injection techniques. Cannulas proved to be associated with a doi: 10.1001/archfacial.2010.65. pdf
lower risk of intravascular injection, but also more precise in predictability of the anatomical layer. 6. Lemperle G, Gauthier-Hazan N, Wolters M, Eisemann- 14. Van Loghem JAJ, Casabona G, Cotofana S. et al.
Klein M, Zimmermann U, Duffy DM Foreign body Consensus on the use of fillers from the Belotero CPM
In Chapter 4, we discuss the reliability of aspiration, a commonly used safety test performed before injection to granulomas after all injectable dermal fillers: part 1. range: best practice in specific facial indications. Final
determine whether the needle is positioned inside a blood vessel, using results from an in-vitro experiment. As soft Possible causes. Plast Reconstr Surg. 2009;123:1842–1963. draft to be submitted in June 2019.
tissue fillers are gel-based and have specific rheologic properties such as cohesivity, viscosity and elasticity, many 7. Funt D, Pavicic T. Dermal fillers in aesthetics: an overview 15. Werschler WP, Narurkar N. Facial volume restoration:
of the tests results were false negative, making aspiration a highly unreliable safety test if no blood is observed in of adverse events and treatment approaches. Clin Cosmet selecting and applying appropriate treatments. Technique
the syringe. The test is reliable with positive aspiration (blood in the hub of the needle), but the high number of false Investig Dermatol. 2013;6:295–316. poster. Cosmet Dermatol. 2006;19(Suppl 2):S1.
negative results may give the injector a false sense of safety. In our study, 67% of aspiration tests within 1 second of 8. Van Loghem J, Yutskovskaya Y, Werschler P. Calcium 16. Beer K, Beer J. Overview of facial aging. Facial Plast Surg.
aspiration were false-negative. hydroxylapatite: over a decade of clinical experience. J 2009;25:281–284.
Clin Aesthet Dermatol. 2014;7:38-49. 17. Decates T, de Wijs L, Nijsten T, Velthuis P. Numbers on
In Chapter 5, we discuss the results of a retrospective analysis of 70 patients who were injected with CaHA in the 9. Hefter H, Hartmann C, Kahlen U, et al. Prospective injectable treatments in the Netherlands in 2016. J Eur
upper third of the face. This area is not a common area for fillers in general, and for CaHA specifically, but with the analysis of neutralising antibody titres in secondary Acad Dermatol Venereol. 2018 Aug;32(8):e328-e330. doi:
suggested blunt cannula techniques, we show that good results with low complication risk can be achieved. non-responders under continuous treatment 10.1111/jdv.14877. Epub 2018 Mar 6.

In Chapter 6, we discuss left versus right side pain perception in 302 patients receiving injectable treatments in the
face, including botulinum toxins and fillers, using a visual analogue pain score. The left side proved more painful,
and the total pain perception was less when injecting the left side first. As pain is the most common side effect with
injectable treatments, it is important that we learn how to minimize it.

In Chapter 7, we describe the results of an advisory board meeting of more than 400 experts from over 60 countries
in which a panel of experts described how to combine soft tissue fillers such as CaHA and HA with botulinum toxin
type A and micro-focused ultrasound with visualization for facial rejuvenation as well as non-facial indications.
Preventative measures including selection of the correct product, the appropriate instrument and the correct
technique are making filler treatments safer, but knowing what to do in the event of a complication is also essential
for patient safety. Therefore, in Chapter 8, we propose comprehensive algorithms for the treatment of complications
that can occur after HA soft tissue filler injections. The algorithms are based on clinical presentation, rather than final
diagnosis, making them relevant for clinical practice.

Along the same lines, in Chapter 9, we report on a consensus statement of a group of international experts on how
to treat vascular complications in the event that they occur after CaHA injection, which currently has no proven
reversing agent.

Finally, in Chapters 10, a consensus group of international experts describe the safest and most effective treatment
techniques for specific HA fillers in the face. Taken together, the findings described in this thesis provide new insights
into Improving patient safety during facial filler treatments in aesthetic medicine.

20 chapter 1 21
 02
Calcium Hydroxylapatite:
Over a Decade of Clinical
Experience

First author. Imact Factor 1.642, SJR 0.605

Published in Journal of Clinical Aesthetic Dermatology. 2015 Jan;8(1):38-49.

Van Loghem JAJ1, Yutskovskaya YA 2, Philip Werschler W3.

1. Depertment of Ophthalmology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. UMA
Institute private practice, Amsterdam
2. Pacific State Medical University of Health Ministry of Russia, Vladivostok, Russia
3. University of Washington School of Medicine, Seattle, Washington

22 chapter 2 23
 abstract
Background Aesthetic medicine has advanced greatly in the past decade in terms of our understanding of facial anatomy; the
cumulative effects of the aging process; and how dermal fillers may be used to repair, reduce, and even reverse
Calcium hydroxylapatite is one of the most well-studied these changes. Initially, aesthetic practitioners were “chasing lines and wrinkles,” based on experience with bovine
dermal fillers worldwide and has been extensively used for the collagen injections beginning in the early 1980s. We now appreciate that a natural and more youthful appearance is
dependent on reversing the cumulative effect of age-related changes both on the surface and in the subsurface tissues.
correction of moderate-to-severe facial lines and folds and to For surface aging, restoration of textural and pigmentary alterations is of paramount importance; for the subsurface,
replenish lost volume. restoring lost volume and shape is the key to the more youthful proportions desired by our patients. This focus on
facial shape and volume to restore balance, symmetry, and the proportions of youth has led to the development and
worldwide clinical use of an ever-expanding list of dermal fillers for treatment of facial aging.
Objectives
Dermal fillers as a category of implantable medical devices, consist of a wide array of products that differ significantly
To mark the milestone of 10 years of use in the aesthetic in their chemical composition, mechanism of action, duration, safety, and interaction with host tissues. Many
different methods of categorization have been proposed, based in part on these differing characteristics; however, no
field, this review will consider the evolution of calcium single, universally agreed upon system exists to date. Of the proposed classification systems, one based on primary
hydroxylapatite in aesthetic medicine, provide a detailed mechanism of action (MOA) first proposed by Werschler and Narurkar has been widely used.1 In this approach,
dermal fillers are placed into categories of either collagen biostimulation or replacement volume as a primary MOA.
injection protocol for a global facial approach, and examine
how the unique properties of calcium hydroxylapatite provide In this schema, Radiesse® (calcium hydroxylapatite; CaHA, Merz Pharmaceuticals GmbH, Frankfurt, Germany) is
a unique product because it provides both replacement volume and collagen biostimulation as a primary MOA. In
it with an important place in today’s market. addition, CaHA is biodegradable and reabsorbed naturally by the host’s metabolic processes. This biostimulatory
MOA, with ultimate reabsorption, results in a performance profile that is unique to Radiesse.

Methods CaHA is a highly effective agent for many areas of facial soft-tissue augmentation and is associated with a well-
established safety profile.2 The year 2013 marked a decade of Radiesse technology, which first received EU approval
This article is an up-to-date review of calcium hydroxylapatite
in 2003 for plastic and reconstructive surgery, including deep dermal and subdermal soft tissue augmentation of the
in aesthetic medicine along with procedures for its use, facial area. In the intervening years, the range of uses for CaHA has evolved alongside developments in the field of
aesthetic medicine from a surface-oriented two-dimensional approach, concentrating on removal of facial lines and
including a detailed injection protocol for a global facial folds, to a three-dimensional approach that also addresses both soft and hard tissue volume loss in both the face and
approach by three expert injectors. the hands.3

With the popularity of dermal fillers demonstrated by increasing numbers of treated patients, public awareness and
Conclusion acceptance of nonsurgical enhancement has greatly increased the treatment options available. Along with botulinum
toxin injections and energy-based devices, fillers are the mainstay of most medical aesthetic clinics. With increasing
Calcium hydroxylapatite is a very effective agent for many areas patient demand and the increased availability of aesthetic providers, private practices have become more competitive.
Patient retention is now a major objective of most aesthetic businesses. Patient satisfaction is a key element for patient
of facial soft tissue augmentation and is associated with a high
retention and requires a portfolio of safe and effective products. Long-term clinical experience, clinical research, peer-
and well-established safety profile. Calcium hydroxylapatite reviewed publications and regulatory approvals have combined to demonstrate the safety and efficacy of CaHA. The
product has been evolved to meet the demands of a continuum of aesthetic care in terms of enhancement of youthful
combines high elasticity and viscosity with an ability to induce patients (ages 25–35); early prevention, rejuvenation, and volume restoration for patients in the middle decades of life
long-term collagen formation making it an ideal agent for (35–55); and for the delay and maintenance as part of restoration for mature (55–75+) patients as well.
In this tenth anniversary year, the authors consider the historical milestones of CaHA in aesthetic medicine, propose
a global facial approach. a protocol for a global facial approach using CaHA, and look at how its unique properties provide it with a place in
today’s market and keep it at the forefront of modern aesthetic treatments. Throughout this publication, reference
is made to labeled and off-label indications, techniques, and dilution protocols performed by experts in the field of
aesthetic medicine. The reader is reminded that some of these are not approved by regulatory authorities and are not
endorsed by Merz Pharmaceuticals GmbH.

24 chapter 2 25
 Mechanism of action Product milestones

Radiesse is a biodegradable filler consisting of 30% synthetic CaHA microspheres (diameter of 25−45μm) suspended Regulatory approvals. Dermal fillers are classified as medical devices by most regulatory agencies (including the
in a 70% aqueous carboxymethylcellulose gel carrier.4 The soluble carrier gel evenly distributes the Radiesse CaHA United States Food and Drug Administration [FDA]) as their primary intended action is mechanical (“filling effect”).
microspheres providing 1:1 correction and gradually dissipates leaving the microspheres at the injection site where Radiesse received a Conformité Européenne (CE) certification mark (medical device class 3) for plastic and
they induce neocollagenesis by fibroblast activation.5−7 In a recent clinical histomorphological study, Radiesse reconstructive surgery, including deep dermal and subdermal soft tissue augmentation of the facial area in 2003. It
significantly stimulated collagen production over nine months of follow-up [Yana Alexandrovna Yutskovskaya, may be injected into the deep dermis, the subcutaneous tissue, or supraperiosteally depending on the area of the face
presented at AMEC, October 12, 2013 and 1st eastern AMWC June 2013]. In this manner, Radiesse provides both being treated. The European label includes, but is not limited to, the nasolabial folds, marionette lines, cheek hollows,
immediate (replacement volume) and long-lasting (collagen biostimulation) volume enhancement. cheekbone, jawline, oral commissures, chin, temple, bridge of the nose, and the hands. In 2006, Radiesse received
FDA approval for the correction of moderate-to-severe facial wrinkles and folds, such as nasolabial folds, and/or the
Fibroblasts are found in all connective tissues and the Radiesse CaHA microspheres are thought to elicit their correction of the signs of facial fat loss in people with human immunodeficiency virus.
activation and subsequent collagen production regardless of whether Radiesse is injected intradermally or at the
level of the dermal−subdermal junction. Animal studies have shown that this new collagen growth occurs as early as Pivotal trials. The clinical use of Radiesse has paralleled developments in the field of aesthetic medicine, which began
four weeks post-injection and continues for at least 12 months.6 A recently performed clinical study has confirmed with a focus on individual facial lines and folds. The pivotal clinical trial that led to the FDA approval of the product
the longevity of collagen stimulation by Radiesse [Yana Alexandrovna Yutskovskaya, presented at AMEC, October for aesthetic correction of nasolabial folds was a multicenter study of 117 subjects with symmetric moderate-to-deep
12, 2013 and 1st eastern AMWC June 2013]. The immediate volume correction as well as stimulation of long-term nasolabial folds.13 Using a randomized, split-face design, subjects were injected with Radiesse on one side of the face
deposition of new collagen surrounding the microspheres contributes to an average duration of effect of 12 to 18 and human collagen (Cosmoplast; Allergan, Irvine, California) on the other. At the six-month evaluation, Radiesse was
months, though some results have been noted 24 months post-injection.8,9 rated as superior to collagen in 79 percent of folds (P<0.0001) and on average required half the amount of material
required for the collagen-treated folds (P<0.0001). An extension of the above study offered re-treatment with Radiesse
As progenitor cells for osteogenesis do not exist in soft tissue, no calcification or osteogenesis has been reported between 6 and 12 months in both folds to balance asymmetry.9 A total of 102 of the initial 117 subjects were enrolled
in extensive literature describing the use of CaHA in a variety of soft tissue applications. CaHA is a completely and evaluated at intervals up to 39 months after the last injection of Radiesse. Of the original 102 subjects, three were
biodegradable soft tissue filler. Over time, the CaHA microspheres are broken down into calcium and phosphate lost to follow-up between the two- and three-year time points. At least 30 months after the last Radiesse treatment,
ions by the phagocytes.10 Further evidence for the biodegradable nature of CaHA is provided by a study in which 40 percent of the folds evaluated remained improved. There were no long-term or delayed-onset adverse events in
computed tomographic (CT) imaging studies were conducted pre- and post-treatment with CaHA in 58 individuals patients followed for up to 39 months, including no reports of nodules, foreign body granulomas, or infections.
with HIv-associated lipoatrophy or pronounced nasolabial folds.11 In the CT scans taken immediately after injection, A second pivotal trial evaluated Radiesse for the treatment of facial lipoatrophy in 100 patients with human
CaHA was clearly visible, whereas 12 months after the initial injection, only residual amounts of CaHA could be immunodeficiency virus receiving highly active antiretroviral therapy. In this open-label study, all subjects reported
observed. It is important to note that in many individuals, the aesthetic effects remained evident at 12 months even significant improvement at 12 months and 91 percent reported significant improvement at 18 months. Quality-of-life
though little CaHA was visible. data collected at 12 months also revealed that 100 percent of subjects had found that Radiesse treatment had been
beneficial.14 Since these trials were conducted, Radiesse has been progressively used for a variety of aesthetic facial
and hand indications.15−17
Physical characteristics
Mixing with lidocaine. In July 2009, a protocol for mixing Radiesse with lidocaine to produce a final lidocaine
The main physical characteristics that determine the ability of injectable fillers to provide volume and lift are complex concentration of 0.3% was approved by the FDA. This was associated with an improvement in patient comfort during
viscosity (η*), elasticity (G'), and cohesivity. the injection process and an increase in patient satisfaction.18 In Europe, this protocol has not yet been approved by
health authorities.
Viscosity. viscosity (η*) measures the ability of a filler to resist the shearing forces that it is subjected to within a tissue
after injection. Radiesse has one of the highest viscosities when compared with other dermal fillers.12 This allows it to Distribution milestone. In 2013, Radiesse reached a distribution milestone with more than five million syringes
remain in the place where it is injected and not to migrate into the surrounding tissue. shipped for a variety of aesthetic indications without any safety concerns. The product is now available in over 50
countries and more than 3,000 patients have received it in controlled clinical studies.
Elasticity. Elasticity (G’) is a measure of a filler’s stiffness and its ability to resist deformation under an applied pressure
that is external to the filler, e.g. when a filler is extruded through a needle during injection and after injection when
the filler is subjected to movements of the facial muscles. The higher the G' the less it deforms under pressure Patient assessment
and the more lift it can provide. Radiesse has a high G' providing it with greater lifting capacity than many other
dermal fillers.12 Patient assessment is one of the most important aspects of a physician’s role as only by making a proper diagnosis can
the appropriate treatment be planned. Assessment of an individual for optimal treatment should include an evaluation
Cohesivity. The lifting capacity of a dermal filler is determined by two material properties: gel hardness (elasticity) of the signs of aging and proportions, harmony, and balance of the face. By combining their knowledge of facial
and the cohesivity of the gel. Radiesse has been developed for optimal lift with a balance between high elasticity anatomy and the aging process, physicians can assess patient suitability and determine the choice of product that will
and cohesivity. ultimately provide the results that each individual patient desires.

Adults of all ages are selecting soft-tissue augmentation, either as a precursor to or as a substitute for surgery. Patients
in different age groups have diverse treatment needs ranging from the correction of fine lines and wrinkles in younger

26 chapter 2 27
 patients to volume restoration in older patients. CaHA is appropriate for a broad range of aesthetic procedures with Table 1
patients’ individual needs dictating the treatment approach. Radiesse injection protocol for a global face approach

Injection protocols for a global facial approach Treatment Area Benefits Injection Protocol Safety Considerations

As well as the development of lines and wrinkles, it is now known that facial volume loss, via a combination of tissue Frontal Reduces Mark frontal concavity prior to Facial nerve, supraorbital/supratrochlear nerve and
laxity (collagen and elastic tissue breakdown), bone resorption (osteopenia of the facial skeleton), and lipoatrophy, all concavity skeletonized injection. arteries. Cannula technique is advised starting from
play an important role in the appearance of aging.19 −22 With this knowledge, the focus of facial aesthetic treatments (parallel and appearance, Inject only at the subgaleal/ temporal crest
has changed from a two-dimensional approach concentrating on removing facial lines and improving skin tone and superior to restores youthful supraperiosteal plane
texture to a three-dimensional approach that also addresses facial volume loss. The correction of volume loss is eyebrows) frontal convexity
performed with an emphasis on the restoration of facial symmetry, balance, and proportion. Radiesse is well suited to and contributes to
this approach as a result of its high elasticity and viscosity, which provide it with an impressive lifting capacity when brow lift
molded and contoured into place. It is also unique among fillers in that the aesthetic results are not just derived from
the volume of product injected, but also from the long-term stimulation of the patient’s own collagen production,5
leading to a longer duration of effect. These physical properties of Radiesse provide it with great versatility and make Temporal Restores oval of Submuscular / supraperiosteal/ Submuscular injection protocol: for Radiesse,
it suitable for most aspects of facial augmentation—line filling, skin tightening, lifting, contouring, and volumizing. concavity the face, reduces subdermal injection protocols aspiration before injection is not a reliable test to
skeletonized avoid intravascular injection as the filler inside the
Studies of saccadic eye movements have revealed the features that people look at when studying a face. Interestingly, appearance and needle will be too viscous to allow blood to enter the
different cultures appear to focus on different face information. For example, Caucasian observers fixate on the eye contributes to lift syringe. Therefore, multiple boluses are injected in the
region and the mouth, whereas East Asian observers fixate more on the central region to extract information from of lateral brow submuscular/supraperiosteal plane.
faces.23 During this scanning of another person’s face, we subconsciously register many different aspects of that With the needle tip gently touching the periosteum, the
person’s anatomy that provide us with quite a precise estimate of that person’s age. As physicians, we need to address chance of intra-arterial injection is minimized. Injector
all of the details that are being scanned in these initial observations to provide our patients with optimal treatment should remain on periosteum during entire injection.
results. To restore a natural more youthful look, a global facial approach is often required to restore the subtle Slow bolus injection minimizes risk of retrograde
variations of side-to-side symmetry, upper-mid-lower face balance, and proportion. Although this article is restricted arterial migration of product and low volume of bolus
to the consideration of CaHA, facial aging is a complex process and a combination of nonsurgical technologies is (0.1–0.2mL per bolus) minimizes risk of necrosis as
typically used to minimize hollows, lines, and wrinkles; recontour features; and improve the skin’s overall tone. It may only a small area could be blocked and will allow for
be stated that the youthful face has more highlights than lowlights, more convexity than concavity, more reflections collateral perfusion. Subdermal injection protocol:
than shadows, and more tone than texture. When undertaking a global facial approach, a multi-level technique venous network, superficial temporal artery. Advisable
generally provides the best results—deep volume restoration at the supraperiosteal level, subcutaneous contour to use blunt cannulas. Injectors often choose to
reconstruction, and superficial dermal reduction of skin laxity (the latter is not an approved indication for Radiesse). dilute according to the FDA dilution protocol (0.3mL
The use of a volumizing filler, such as CaHA can immediately restore volume as well as fill and correct specific lidocaine for a 1.5mL Radiesse syringe)
creases and hollows. It is ideal for use in all areas of the face except the glabella, superficial periorbital area, and lips.
The amount injected will vary depending on the site and extent of the restoration or augmentation desired, but in all
cases, the correction ratio for Radiesse is approximately 1:1 (i.e., overcorrection should be avoided). Brow lift Lifts brow, Submuscular / supraperiosteal Venous plexus, supraorbital artery and nerve,
reduces lateral or subcutaneous / dermal intraorbital area. Avoid masculinization of the female
A detailed injection protocol for a global facial approach is provided in Table 1. In the upper face, sunken temples and hooding injection at the level of the lateral brow: limit volume.
the area above the eye brows (frontal concavity) can be significant contributors to an aged look. Volume restoration brow to the peak/middle of A cannula is advised to avoid intravascular injection.
with CaHA can return a youthful appearance to these areas and even raise the outer brow (Figures 1 and 2). The outer the brow. Needle or cannula If a needle is used, inject with: 1) low volume, 2) low
edge of the eyebrows can sometimes droop with age. The addition of a small amount of Radiesse to this area provides technique. Our technique is only pressure, 3) retrograde in an area where there are no
a very subtle lift to the brow by restoring volume to a tiny fat pad located directly underneath the eyebrow (Figure 3). for supraperiosteal placement, large arteries—the dermal/subdermal plane of the area
This technique may be especially effective when used in combination with botulinum toxin to relax the muscles that as vas- cular entry / cannulation from the peak to the tail of the brow; more medially from
pull the brow down (lateral brow depressors). is too much of a risk in this area. the peak, direct arterial connections to the intra-orbital
area are present (supraorbital artery, supratrochlear
In the midface, restoring volume to the cheekbone and the sunken area beneath the cheekbone (submalar hollowing) artery). Also avoid deep injection to prevent intra-
returns the face to a younger heart shape (triangle of youth) and is a subtle way of making a patient look and feel arterial injection. Advocate no more than 0.3mL total
younger (Figure 4). The effect is to lift sagging soft tissues, reduce lower eyelid lag, and reduce the tear trough without volume to brow in a single injection sitting.
the need for treating the tear trough area. Adding volume to the cheekbones (midface) also provides lift to the cheek
and jowls (lower face). Above the alar-tragal line (Hinderer’s line), CaHA should be injected supraperiosteally, while
below the alar-tragal line, injection should be at least deep dermally to the junction with the subcutis. Continued on next page

28 chapter 2 29
 Treatment Area Benefits Injection Protocol Safety Considerations Treatment Area Benefits Injection Protocol Safety Considerations

Zygomatic area Restores V-shape Multilevel approach: Needle or Infraorbital foramen; lymphatic drainage, infraorbital fat Mandibular Cheek laxity can cause ptosis of the gland into the
of the face, cannula technique. Cannula: 2- compartments, malar edema. augmentation injection area. Advocate supraperiosteum placement
restores youthful point technique: Zygomatic arch Proper patient selection is necessary, for example, (continued) with minimal massage to avoid retrograde tracking
cheek convexity, entry point and medial zygoma care should be taken when treating patients with fat into needle track. If placing a few subdermal product
lifts sagging soft entry point bags. Assess for any asymmetry of the zygomatic threads, care should be exercised to stay immediately
tissues, reduces Above alar-tragal line: Inject only arches in each patient. Augmentation of the midface in subdermal to avoid inadvertent injection into the
lower lid lag, and at the periosteal level. Below individuals with herniated fat pads may help to reduce parotid.
reduces tear alar- tragal line: Inject more “su- the appearance of fat pads. However, care should be Masseter muscle—Product placement should be
trough (without perfi- cially” (meaning dermal/ taken not to inject into the Arcus Marginalis, as this below this muscle
treating the latter). subdermal junction) may result in protrusion of the fat, and development Facial artery—Palpate this artery medial to the
of “white bangers” as Radiesse aggregates and masseter muscle in the antigonal notch along the
becomes visible through the skin. inferior edge of the mandible. Nicking this artery is a
Note: Avoid injection of product directly into a fat pad, common cause of increased bruising in the area
as fat pads are quite vascular. Advocate injection only Facial nerve—This nerve runs through the parotid
over periosteum and lightly mold when complete gland. Avoid injection in or near the parotid gland
• Palpate angle of the jaw and outline with a skin pencil.
Mandibular Restores mandi- 2-point cannula technique. Mandibular angle: Facial arteries; avoid placing product Palpate the facial artery located immediately anterior
augmentation bular definition, Mandibular angle: Placement at into jowl, as that might aggravate jowling. Parotid gland. to the masseter muscle. May have patient clench their
reduces jowl, pre- dermal/subdermal junction for Pre-jowl sulcus entry point: mental foramen, avoid pla- jaw to palpate the anterior edge of masseter. Mark this
jowl sulcus, and skin tightening and redefining cing product into mucosa and muscle as intramuscular area with an “X” to indicate a non-injection area. Mark
marionette lines mandible. injection can lead to nodule formation. the desired locations to place aliquots on the angle of
Point (depot) technique at the the jaw
mandibular angle may help to Pre-jowl sulcus (PJS) injection • Suggested aliquot locations: Near the angle of the
define the lateral jaw, especially • Palpate edge of mandible and position finger under jaw, slightly anterior to the angle of the jaw, superior
in older patients and those with edge of mandible to prevent inadvertent tracking of overlying the inferior portion of the ramus. Note any
poorly defined definition from product inferiorly upon injection asymmetry pre-injection
face to neck, and contribute to • Select PJS insertion point (antero-superior to the • Position thumb under edge of mandible and use
curvilinear mandibular sweep. mandibular edge, mid PJS defect), advance needle fingers of noninjecting hand to push soft tissue
Pre-jowl sulcus entry point: down to periosteum being aware of bevel opening structures up and off the mandibular edge to prevent
Multilevel technique (dermal/ • Inject aliquot of product (up to 0.4mL) to periosteum in inadvertent tracking of product inferiorly or into the
subdermal junction plus supra- the direction you wish to augment the pre-jowl sulcus parotid gland upon injection
periosteal placement). Suprape- concavity: Example: if injecting on the lateral edge of • Select insertion point for aliquot nearest the angle of
riosteal placement to augment the concavity, have the bevel opening facing medially. the jaw by rolling finger to locate slight concavity. At a
masseter projection • May reposition needle to change bevel opening and 90 degree angle to the skin, advance needle down to
flow of product, depending on visual endpoint/desired periosteum and place an aliquot of product (up to 0.5mL)
correction. Example: after the first bolus is placed, it • A total of 0.7–2.95mL of Radiesse has been used to
is not uncommon to reposition the bevel opening to treat each AOJ, depending on correction desired
face superomedially in order to place a smaller bolus to • Place next aliquot just superior to first along the lateral
complete the desired correction/augmentation. edge of ramus. Aliquot volume should decrease as
• May add subdermal threads if collagenesis is desired additional aliquots are placed
over the pre-jowl sulcus aspects. • Third aliquot may be placed medial to angle site. Care
• Gently pinch and mold to further contour jaw line should be taken to avoid the antigonal notch, facial
artery, and nerve
Angle of jaw (AOJ) injection • May place linear threads in the subdermal plane for
• Parotid gland —Avoid injection into this gland, which contouring between aliquots. Gently pinch and mold to
lies within the lateral cheek fat medial to the ear. further contour jaw line and smooth product

Continued on next page Continued on next page

30 chapter 2 31
 Treatment Area Benefits Injection Protocol Safety Considerations

Mentum Reduces Multi-level approach: Submental artery. Avoid injecting in the oral mucosa,
augmentation marionette lines, submuscular at the periosteum so supraperiosteal injection only when injecting
restores convexity of the mentum and dermal/ submuscularly.
of mentum, subdermal junction. 1-point Typical injection is subdermal. Care must be taken
balances the face cannula technique when injecting to periosteum at this level, given the
with Steiner’s line product may show or surface to the lower gingival
(joins soft tissue sulcus immediately following injection (physician
pogonion to the thought he/she was lower than the gingival sulcus
mid- point between and was not). Total volume injected during a single
subnasal and nasal treatment session is often around 0.5mL per side
tip; the lips should
touch this line)

In the lower face, the jawline loses its curvilinear (oval) shape and smooth line with age. Recommended insertion
points for recontouring the jawline and disguising the jowls are at the mandibular angle and prejowl sulcus, and
CaHA should be placed at the dermal−hypodermal junction or deep dermis (Figure 5). Augmentation of the mandible Figure 1
just supraperiosteally below the masseter (mandibular angle) is effective in both men and women, where loss of Frontal concavity. The danger point (supraorbital foramen) is marked and should be avoided as there is
volume of the masseter and mandible can be simultaneously addressed. The use of CaHA for mentum augmentation a direct access to the intraorbital area. 38 The cannula entry point is chosen at the temporal crest, lateral
alters the projection of the chin and reduces marionette lines, providing noticeable improvements to an individual’s to the frontal concavity. The cannula is advanced through the muscle, through the galea aponeurotica
appearance (Figure 6). At the mentum, a multi-level approach is also recommended, where supraperiosteal placement and advanced in the glide plane between the galea and the periosteum of the frontal bone. Radiesse is
is combined with dermal/ subdermal placement. deposited in retrograde linear threads.

A set of consensus recommendations on the use of CaHA for jawline rejuvenation has recently been published,
which reinforces the approach described above.24 The recommendations use a validated jawline scale for defining
loss of oval facial contours to provide clinicians with step by step guidance on jawline rejuvenation with CaHA,
including advice on type of anesthesia, injection techniques, volume for injection, and use in combination with
other procedures.

32 chapter 2 33
 Figure 2
Sunken temples. The danger zone is marked in red: Intravascular injection into the superficial temporal Figure 4
artery should be avoided while injecting with a needle. At the point of maximum depression, the needle Zygomatic area. The danger zone (infra-orbital foramen) is marked in yellow and the marking at the infra-
is placed perpendicular to the skin and advanced slowly until contact with the periosteum is felt. Slow orbital rim serves as a reminder of the cranial limit of this area. For the augmentation of the cheek, a two-point
injection of small amounts of Radiesse will maximize safety. There is evidence of small arteries running cannula technique is advised. As a general rule of thumb, the injections cranial to the alar-tragal line should
over the periosteum so there is a theoretical risk of intra-arterial injection. Slow injection reduces the risk of be placed at the supraperiosteal level, whereas the injections below this line should be placed at the level of
retrograde displacement and embolization of intraorbital (including retinal) arteries. Low volume injection the dermal-subdermal junction. The first entry point is found between the superior and inferior demarcation
minimizes necrotic area. Due to supraperiosteal placement, the temporal muscle, which is connected by of the zygomatic arch, immediately in front of the hair line. From this point, a vector line can be drawn to the
loose connective tissue, is hydrodissected from the periosteum. oral commissure. At the intersection of the vector line and the alar-tragal line, the second entry point can be
found. Left: Before with markings; middle: Before; right: After 1.5mL Radiesse per side in the cheeks.

Figure 3 Figure 5
Brow lift. The danger zone (supra orbital foramen) is marked in red. The entrance for the cannula is chosen Mandibular augmentation. As bone resorption is most apparent at the dorsum of the mandible, at the
at the tail of the brow. A multi-level approach is used with one or two retrograde linear threads at the dermal- mandibular angle, the cannula entry point for mandibular augmentation should be placed at the dorsum of
subdermal junction and two additional retrograde linear threads at the periosteal plane on the orbital rim. the mandibular angle. 22 From there, the cannula should be advanced at the level of the dermal-subdermal
With female patients in particular, care should be taken not to overcorrect here to avoid masculinization junction to the pre-auricular area, from where a fanning technique can be used with diluted Radiesse for
(max 0.15–0.2mL for the lateral brow). easier spreading of the product (in this case 0.8mL lidocaine per 1.5mL Radiesse). To enhance definition
of the mandible, the first and last thread can be made with more volume (e.g., 0.2–0.3mL). Care should be
taken to avoid placing Radiesse into the jowl fat compartment, as this can aggravate the aged appearance.
To improve the mandibular area further, Radiesse can be placed in the marionette lines and mental crease
via the pre-jowl sulcus entry point as shown.
Left: Before with markings; middle: Before; right: After 1.5mL Radiesse in the jawline plus marionette lines.

34 chapter 2 35
 Needle or cannula

Dermal fillers may be injected using either a hypodermic needle or blunt-tip microcannula. CaHA is generally
injected with a 30mm-long 27 gauge or 19mm-long 28 gauge inner diameter needle or a 25 or 27 gauge variable
length microcannula. Needles have the advantage of extreme precision of movement, the possibility of deep
intradermal injection, and a requirement for smaller injection volumes. Disadvantages of needles include pain,
bruising, and nerve/vessel laceration. Cannulas cause less trauma, pain, and bruising and allow a large area to be
treated at the chosen injection depth.

When using a microcannula, the authors suggest first making a stab incision with a needle that is 1 to 2 gauges thicker
than the cannula. The cannula should then be inserted while stretching the skin to open the needle aperture. The
cannula should be twisted and rotated until any resistance has passed. When the cannula is through the dermis the
skin in front of the cannula should be pinched in order to go deeper, or the skin should be stretched in the direction of
the cannula for superficial injections (one finger in front and one finger behind the cannula).
Figure 6
Mentum augmentation. For augmentation of the mentum, a multi-level approach is generally used. In this
case, a cannula was inserted at the pre-jowl sulcus entry point and advanced in both the supraperiosteal Dilution
layer, as well as the junction between the dermis and subcutis. Augmentation was continued until the
patient had a good Steiner Line. 39 Left: Before with markings; middle: Before; right: After 1.5mL Radiesse in The FDA has approved a protocol for mixing Radiesse with lidocaine. This makes the experience more pleasant
the mentum. for patients, which will keep them motivated to return for additional treatments. In addition, the treatment
site is anesthetized as the injection process progresses, which eliminates distortion of the treatment site from
local anesthetic.

An additional benefit of the mixing protocol is that CaHA with 0.3% lidocaine is easier to extrude from the needle
than CaHA alone. A rheometric study of several hyaluronic acid (HA) fillers and Radiesse found that Radiesse alone
had the highest G' and viscosity, followed by Radiesse diluted with 0.3% lidocaine, Perlane® (Galderma) and
Restylane® (Galderma) in the medium group, and the Juvederm® (Allergan) product family in the low G' and viscosity
group.12 When mixing with lidocaine, the viscoelastic properties of the gel change, at least temporarily, for any dermal
filler. Sundaram et al12 showed that when mixing with 20% by volume lidocaine (as per the FDA-approval study18), the
viscosity and elasticity of Radiesse are slightly reduced. It is therefore important to refer to the FDA-approved protocol
for mixing Radiesse and lidocaine as this represents the optimal protocol for preserving the viscoelastic properties of
the product.

The addition of lidocaine adjusts the cohesiveness of CaHA to make it suitable as a layering rather than volumizing
filler while also allowing the use of smaller needles. Some expert injectors use different volumes and dilutions of
CaHA to perform distinct roles when augmenting the face. For example, undiluted CaHA may be injected at a deep
level just above the periosteum to replenish volume loss, a slightly diluted CaHA may be used to restore contours
and proportions at the subcutaneous level, and an even more diluted version may be injected into the dermis and
subdermis to reduce skin laxity and provide the patient with a smoother, more radiant complexion. The above
can also be performed as individual treatments, depending on the patient’s needs and desires. Some injectors use
lidocaine for the initial dilution to reduce discomfort with further dilutions achieved by adding normal saline solution.
A common choice of many injectors is to use lidocaine premixed with adrenaline. The advantage of this approach is
that the vasoconstriction triggered by adrenalin reduces post-treatment edema.

It should be noted that while dilution of CaHA is a method of titrating its viscosity and expanding its use to
applications that require more superficial placement and greater product spread (e.g., fine lines, dorsum of the hand),
the technique is not approved for this purpose and its use in this manner must therefore be regarded as off-label.

36 chapter 2 37
 discussion
Safety Radiesse is a very effective agent for many areas of facial soft tissue augmentation and is associated with a high and
well-established safety profile.32 It is currently the only resorbable filler on the market that immediately replenishes
Radiesse has been extensively used for the correction of moderate-to-severe facial lines and folds and to replenish lost lost volume while at the same time stimulating the production of the skin’s natural collagen for long-lasting results.
volume. The Radiesse CaHA microspheres are smooth in shape and identical in composition to a mineral component Treatment effects have been clinically proven to last a year or more in many patients. Only one other filler has been
of human bone and teeth and are thus inert and nonantigenic. In the pivotal clinical trials that led to FDA approval of shown to stimulate new collagen formation, but the polymethylmethacrylate (PMMA) microspheres of ArteFill®
Radiesse for aesthetic correction, adverse events were generally mild (bruising, edema, erythema, pain, and pruritis) (Suneva Medical) are permanent and not resorbed.
and short in duration.13,14 In the trial comparing Radiesse- and collagen-treated patients, there was no significant
difference in adverse event rates or duration.13 There have been no reports of granuloma formation in studies The unique characteristics of Radiesse (high elasticity and viscosity, combined with its ability to induce long-term
injecting Radiesse for aesthetic use.9,16,25−28 Rare incidences of untoward foreign body reactions with CaHA have been collagen formation) provide it with great versatility, and its use has evolved in parallel with developments in the
described in only a handful of case reports in over 10 years of clinical use29−31 and in none of these cases could any aesthetic field from an agent for simple line filling to one that can be used for a global facial approach. As a result,
definite conclusions be drawn as to whether the events were related to Radiesse or other circumstances (i.e., treatment Radiesse is appropriate for treating patients at any stage of the aging process. To date, more than five million syringes
with other, permanent fillers in the past, improper tissue placement, medical history, etc.).32,33 Indeed, the literature have been shipped for a variety of aesthetic indications. Radiesse is approved for aesthetic use in more than 50
frequently describes case reports of dermal filler complications without adequate proof that the alleged material was countries, including the United States, where the FDA has the most rigorous criteria for filler approvals worldwide.
actually injected.34 Adverse events that do occur with CaHA are usually temporary and injection-related (e.g., bruising
and edema). As with all dermal fillers, most adverse events are avoidable with proper planning and technique. Off-label uses of drugs and devices are commonly practiced by physicians in consultation with patients in virtually
every area of medicine, and the aesthetic field is no exception. Furthermore, what constitutes an off-label use in
one country may be an approved indication in another. Expert injectors continue to expand the potential uses for
Radiesse with additional as yet off-label indications and techniques for diluting and injecting more superficially. Most
recently, this involves hyperdilution of the product so that it can be used very superficially for skin tightening. [Yana
Alexandrovna Yutskovskaya, unpublished data]. A further off-label indication involves placing the product under
the hair, below the galea, to correct bone resorption of the frontal bone and to lift the forehead [Jani van Loghem,
unpublished data]. While off-label procedures such as these are not approved by regulatory authorities and are not
endorsed by Merz Pharmaceuticals GmbH, in the hands of expert injectors they can be regarded as innovation in
medicine and will likely lead to new and better treatments and procedures in the future.

An important issue, however, is the skillset of individuals performing the procedures, particularly non-physician
injectors who may also have a limited knowledge of facial anatomy. Nodule formation can occur after injection of
CaHA into the oral mucosa and the lips.2 The injection of CaHA in this highly mobile area may cause the CaHA
particles to clump and is not an approved indication nor is it approved by Merz. The nodules occur soon after
injection and are a result of accumulated particles and not a granulomatous reaction. They are completely resolved
with injection of saline and vigorous massage35 or with the use of fractional carbon dioxide laser therapy.36 Special
care should be taken to avoid injection of any filler into a blood vessel. This may occlude the vessel and could cause
infarction or embolism leading to ischemia, necrosis, or scarring. Although rare, cases have been reported with a
number of dermal fillers including CaHA.37 They are all related to poor injection technique and not filler product.

Physician experience is essential for satisfied patients, and is being addressed by leading pharmaceutical companies
in the aesthetic field (e.g., by the unique service of Field Clinical Specialists offered by Merz Pharmaceuticals GmbH).
These are medical professionals who conduct intensive individual training of aesthetic physicians to ensure best
practice in the aesthetic industry and best outcomes for patients. Radiesse has emerged as a versatile, durable, and
safe filler. It has an excellent volumizing effect for a variety of aesthetic indications, and its use is only anticipated to
grow as more clinicians and patients gain first-hand experience with it.

38 chapter 2 39
 references
1. Werschler WP, Narurkar N. Facial volume restoration: 11. Carruthers A, Liebeskind M, Carruthers J, Forster BB. anatomy and clinical implications for cosmetic surgery. filler. Oral Surg Oral Med Oral Pathol Oral Radiol.
selecting and applying appropriate treatments. Technique Radiographic and computed tomographic studies of Plast Reconstr Surg. 2007;119:2219–2227. 2012;114:107–111.
poster. Cosmet Dermatol. 2006;19(Suppl 2):S1. calcium hydroxylapatite for treatment of HIv-associated 20. Rohrich RJ, Pessa JE. The retaining system of the face: 31. Moulonguet I, Arnaud E, Bui P, Plantier F. Foreign body
2. Tzikas TL. A 52-month summary of results using calcium facial lipoatrophy and correction of nasolabial folds. histologic evaluation of the septal boundaries of the reaction to Radiesse: 2 cases. Am J Dermatopathol.
hydroxylapatite for facial soft tissue augmentation. Dermatol Surg. 2008;34(Suppl 1):S78–S84. subcutaneous fat compartments. Plast Reconstr Surg. 2013;35:e37–e40.
Dermatol Surg. 2008;34(Suppl 1):S9–S15. 12. Sundaram H, voigts B, Beer K, Meland M. Comparison of 2008;121:1804–1809. 32. Pavicic T. Calcium hydroxylapatite filler: an overview of
3. Carruthers JD, Glogau RG, Blitzer A; Facial Aesthetics the rheological properties of viscosity and elasticity in two 21. Gierloff M, Stöhring C, Buder T, et al. Aging changes of safety and tolerability. J Drugs Dermatol. 2013;12:996–
Consensus Group Faculty. Advances in facial rejuvenation: categories of soft tissue fillers: calcium hydroxylapatite the midfacial fat compartments: a computed tomographic 1002.
botulinum toxin type A, hyaluronic acid dermal fillers, and and hyaluronic acid. Dermatol Surg. 2010;36(Suppl study. Plast Reconstr Surg. 2012;129:263–273. 33. Werschler WP. Response to “Oral lesions associated with
combination therapies—consensus recommendations. 3):1859–1865. 22. Shaw RB, Katzel EB, Koltz PF, et al. Aging of the facial injected hydroxyapatite cosmetic filler.” Oral Surg Oral
Plast Reconstr Surg. 20. 2008;121(5 Suppl):5S–30S. 13. Smith S, Busso M, McClaren M, Bass LS. A randomized, skeleton: aesthetic implications and rejuvenation Med Oral Pathol Oral Radiol. 2013;115:417–419.
4. Graivier MH, Bass LS, Busso M, et al. Calcium bilateral, prospective comparison of calcium strategies. Plast Reconstr Surg. 2011;127:374. 34. Freshwater MF. Was it really Radiesse or whose algorithm
hydroxylapatite (Radiesse) for correction of the mid- and hydroxylapatite microspheres versus human-based 23. Blais C, Jack RE, Scheepers C, Fiset D, Caldara R. Culture is better? J Plast Reconstr Aesthet Surg. 2014;67:569–570.
lower face: consensus recommendations. Plast Reconstr collagen for the correction of nasolabial folds. Dermatol shapes how we look at faces. PLoS One. 2008;3:e3022. 35. Voigts R, Devore DP, Grazer JM. Dispersion of calcium
Surg. 2007;120(6 Suppl): 55S–66S. Surg. 2007;33:S112–S121. 24. Dallara JM, Baspeyras M, Bui P, Cartier H, Charavel hydroxylapatite accumulations in the skin: animal studies
5. Marmur ES, Phelps R, Goldberg DJ. Clinical, histologic, 14. Silvers SL, Eviatar JA, Echavez MI, et al. Prospective, open- MH, Dumas L. Calcium hydroxylapatite for jawline and clinical practices. Dermatol Surg. 2010;36:798–803.
and electron microscopic findings after injection of label, 18-month trial of calcium hydroxylapatite (Radiesse) rejuvenation: consensus recommendations. J Cosmet 36. Reddy KK, Brauer JA, Anolik R, et al. Calcium
a calcium hydroxylapatite filler. J Cosmet Laser Ther. for facial soft tissue augmentation in patients with human Dermatol. 2014;13:3–14. hydroxylapatite nodule resolution after fractional carbon
2004;6:223–226. immunodeficiency virus associated lipoatrophy: one year 25. Moers-Carpi M, vogt S, Santos BM, et al. A multicenter, dioxide laser therapy. Arch Dermatol. 2012;148:634–636.
6. Coleman KM, voigts R, Devore DP, Termin P, Coleman durability. Plast Reconstr Surg. 2006;118(Suppl):34S–45S. randomized trial comparing calcium hydroxylapatite to 37. DeLorenzi C. Complications of injectable fillers, part 2:
WP 3rd. Neocollagenesis after injection of calcium 15. Jansen DA, Graivier MH. Evaluation of a calcium two hyaluronic acids for treatment of nasolabial folds. vascular complications. Aesthet Surg J. 2014;34:584–600.
hydroxylapatite composition in a canine model. Dermatol hydroxylapatite-based implant (Radiesse) for facial Dermatol Surg. 2007;33(Suppl 2):S144–S151. 38. Pessa JE, Rohrich RJ. Facial Topography. Clinical Anatomy
Surg. 2008;34(Suppl 1):S53–S55. soft tissue augmentation. Plast Reconstr Surg. 26. Beer K, Yohn M, Cohen JL. Evaluation of injectable of the Face. St Louis, Mo: Quality Medical Publishing Inc;
7. Berlin AL, Hussain M, Goldberg DJ. Calcium 2006;118(Suppl):22S. CaHA for the treatment of mid-face volume loss. J Drugs 2012.
hydroxylapatite filler for facial rejuvenation: a histologic 16. Sadick N, Katz BE, Roy D. A multicenter, 47-month study Dermatol. 2008;7:359–366. 39. Erbay EF, Caniklioğlu CM, Erbay SK. Soft tissue profile in
and immunohistochemical analysis. Dermatol Surg. of safety and efficacy of calcium hydroxylapatite for soft 27. Siclovan HR, Jomah JA. Injectable calcium hydroxylapatite Anatolian Turkish adults: Part I. Evaluation of horizontal
2008;34(Suppl 1):S64–S67. tissue augmentation of nasolabial folds and other areas of for correction of nasal bridge deformities. Aesthetic Plast lip position using different soft tissue analyses. Am J
8. Jacovella PF. Use of calcium hydroxylapatite (Radiesse®) the face. Dermatol Surg. 2007;33:S122–S127. Surg. 2009;33:544–548. Orthod Dentofacial Orthop. 2002;121:57–64.
for facial augmentation. Clin Interv Aging. 2008;3:161– 17. Sadick NS. A 52-week study of safety and efficacy of 28. Rokhsar C, Ciocon DH. Nonsurgical rhinoplasty: an
174. calcium hydroxylapatite for rejuvenation of the aging evaluation of injectable calcium hydroxylapatite filler for
9. Bass LS, Smith S, Busso M, McClaren M. Calcium hand. J Drugs Dermatol. 2011;10:47–51. nasal contouring. Dermatol Surg. 2008;34:944–946.
hydroxylapatite (Radiesse) for treatment of nasolabial 18. Marmur E, Green L, Busso M. Controlled, randomized 29. Sankar v, McGuff HS. Foreign body reaction to calcium
folds: long-term safety and efficacy results. Aesthet Surg J. study of pain levels in subjects treated with calcium hydroxylapatite after lip augmentation. J Am Dent Assoc. Reproduced with permission. van Loghem et al. Calcium
2010;30:235–238. hydroxylapatite premixed with lidocaine for correction of 2007;138:1093–1096. hydroxyapatite: Over a Decade of Clinical Experience. J
10. Bentkover S. The biology of facial fillers. Facial Plast Surg. nasolabial folds. Dermatol Surg. 2010;36:309–315. 30. Daley T, Damm DD, Haden JA, Kolodychak MT. Oral Clin Aesthet Dermatol 2015;8(1):38–49. Copyright 2015
2009;25:73–85. 19. Rohrich RJ, Pessa JE. The fat compartments of the face: lesions associated with injected hydroxyapatite cosmetic Matrix Medical Communications. All rights reserved.

40 chapter 2 41
 03
Cannula Versus Sharp Needle
for Placement of Soft Tissue
Fillers: An Observational
Cadaver Study

First author. Impact Factor 2.697, SJR 1.434

Published in Aesthetic Surgery Journal. 2016 Dec 16. pii: sjw220.

Van Loghem JAJ1, Humzah D2, Kerscher M3.

1. Depertment of Ophthalmology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. UMA
Institute private practice, Amsterdam, Netherlands
2. West Midlands Hospital, Halesowen, West Midlands, United Kingdom
3. Department of Chemistry, University of Hamburg, Hamburg, Germany

42 chapter 3 43
 abstract
Background Results
Soft-tissue fillers have become important products for The non-traumatic cannula technique resulted in product
facial rejuvenation. Deep fat compartments and facial being confined to the deep anatomic layers. In contrast,
bones lose volume during the natural aging process. with the sharp needle technique, material was placed in
For the most natural-looking results, deep volumetric multiple anatomic layers, from the periosteum to more
injections at strategic sites are therefore preferred. superficial skin layers. For both techniques results were
Supraperiosteal placement is performed with consistent for all facial sites.
a sharp needle or a non-traumatic cannula.
Conclusions
Objectives Although direct extrapolation from cadavers to the in
The primary objective was to determine whether there vivo situation cannot be made, cannulae showed more
is a difference in precision between supraperiosteal precision in placement of product. With the sharp needle,
placement with a sharp needle compared with a non- the material was injected on the periosteum, and then
traumatic cannula in cadaver specimens. A secondary migrated in a retrograde direction along the trajectory of
objective was to analyze the safety profiles of both the needle path, ending up in multiple anatomic layers. The
injection techniques. sharp needle technique also showed a higher complication
risk with intra-arterial injection occurring, even though
Methods the needle tip was positioned on the periosteum and the
Cadaver heads were injected with dye material and product was injected with the needle in constant contact
soft-tissue fillers at multiple aesthetic facial sites on with the periosteum.
the supraperiosteum and subsequently dissected for
observation of dye and filler placement.

44 chapter 3 45
 introduction methods
In a market where patients are less willing to undergo considerable downtime and do not want a major surgical To assess current opinion concerning the safety and precision of needles vs. cannulas and to determine which needle
procedure, the demand for soft-tissue fillers is increasing.1,2 According to data from the American Society for Aesthetic and cannula injection techniques are used most frequently, a poll of expert injectors (plastic surgeons, dermatologists
Plastic Surgery (ASAPS), more than 2.1 million hyaluronic acid filler treatments were performed in 2015, making them and aesthetic physicians) was conducted. Injectors were recruited from the personal contacts of one of the authors
the second most popular nonsurgical cosmetic procedure performed in the USA after neuromodulators; the latter (JvL) and asked to complete a web-based questionnaire. Using the FSQM Pro Wordpress plugin, the entries were
procedure is frequently performed in concert with soft-tissue filler injections.3 stored in a database and analyzed. The online poll was left open for 7 days before downloading the results.

At the forefront of developments in aesthetic medicine, physicians have advanced beyond filling rhytides and are Two thawed, previously frozen, unembalmed cadaver heads (one male, 85 years old and one female, 92 years old)
now targeting specific facial sites for deep volumetric augmentation.4,5 Evidence for significant volume loss in specific were provided for a single day dissection study in March 2015 by the Skills Lab of the Academic Medical Center
deep fat compartments and facial bones during the aging process is well documented in the medical literature.6-8 The in Amsterdam (consent for the use of still images for this article was provided by the department of Anatomy,
aging process occurs in all anatomical layers of the face and rejuvenation should therefore not be limited to dermal Embryology and Physiology; consent for the use of recorded video was only provided for offline use at congresses
signs of aging.7 Injection of fillers at strategic target sites can reconstruct a youthful anatomy and thereby provide the and scientific meetings). The individuals had consented to the scientific and medical use of their bodies prior to
patient with a natural result. As the relatively new field of aesthetic medicine develops, practitioners are using filler their deaths.
products and techniques with established safety profiles to reduce complications and to increase patient satisfaction.9
To provide natural-looking results, the physician must have a thorough knowledge of the anatomical changes taking The following aesthetic indication sites were marked: frontal concavity, temporal hollows, tear troughs, the lateral
place during the aging process and be able to place fillers in the specific target areas that have lost volume.10,11 The mandible, and the mentum. The marked areas were injected with either a non-traumatic cannula (25G, 50mm
practitioner should also be aware of the key anatomical features of each injection site and choose an injection Steriglide, TSK Laboratory, Japan) with retrograde treads, or a short, sharp needle (25G, 25mm, Terumo, Belgium). A
technique that is safe and effective.12-14 longer sharp needle was used when tissue thickness demanded this (27G, 40mm, Terumo, Belgium). With the sharp
needle, a supraperiosteal bolus technique was used. This involved positioning the needle tip perpendicular (60-90
The facial arterial system in particular, represents a danger zone for filler injections, as intra-arterial injection can degrees) to the skin, advancing until there was direct contact with the periosteum, and then injecting the material
potentially lead to widespread necrosis and even blindness.13-15 Blindness can occur by injection in an artery in with the needle remaining in direct contact with the periosteum. No hydro-dissection with saline or lidocaine was
proximity to the orbit and requires rapid specialist intervention. Minimizing the risk of intra-arterial injection of fillers performed at the supraperiosteal level prior to injection.
is therefore of paramount importance.14,15
To facilitate passage of the non-traumatic, blunt cannula through the dermis, an opening was first made using a 23G
Technological developments include the introduction of the blunt-tipped, or non-traumatic cannula as an alternative sharp needle. In one area (temporal hollows), a thicker gauge needle was used (20G) to make the pre-hole, as this
to the sharp needle. With a sharp needle, placement of the needle tip is considered very precise. It is therefore made it easier to pass through the deep temporal fascia. With this technique the cannula was inserted into the tissue
assumed that positioning the tip at the periosteum is relatively easy and will result in precise placement of filler at an oblique angle to the skin (10-45 degrees). The injections were performed by two of the authors (JvL & DH). The
product.16 However, final placement of the filler at this level cannot be guaranteed. aim of both techniques was to place colored acrylic dye (Royal Talens, Apeldoorn, Netherlands) on the periosteum,
avoiding adjacent danger zones. After injection, the aesthetic zone was lightly massaged and dissected (DH) layer by
Treatment with non-traumatic cannulas results in significantly fewer bruises and lower pain scores, and is gaining in layer to determine whether any product was present in more superficial layers, and whether any product was in or
popularity.17 However, non-traumatic cannulas are more difficult to manoeuvre to the periosteal level and cannula near an arterial danger zone. To minimize spread of the colored material by mechanical effects of the dissection, a
techniques are therefore wrongly regarded as less precise than those using a needle. Placing the tip of a sharp careful layer-by layer dissection was performed from superficial to deep, without putting any pressure on the tissue.
needle on the periosteum is often thought to be a safe technique to avoid intra-vascular embolization for two main The chosen dye was thick and paste-like and therefor had less tendency to accidentally contaminate the adjacent
reasons. First, there are very few arteries running over the periosteum, making it almost an avascular area. Second, areas during the dissection, than more liquid colored alternatives.
it is assumed that a needle with an artery in its trajectory, will completely pierce the artery and exit the other side,
avoiding injection of product in the lumen of the artery. The first cadaver dissection session was recorded on high-definition video from which high-quality still images were
obtained. The final edit took 3 weeks to complete at which point the authors could review the video recordings and
In this cadaver dissection study, our aim was to determine the final position of injected product using sharp needle export the still images. Two of the authors were then asked to individually determine in which anatomical layers the
versus non-traumatic cannula techniques in a split-face approach. A secondary aim was to study the safety profiles of dye was observed. The layers in which the dye was observed were determined for each instrument and the results
both injection techniques, related to adjacent arterial danger zones. were pooled for the two observing physicians to determine whether there was any statistical difference between the
two groups (sharp needle / perpendicular approach vs. blunt cannula / oblique approach). The Pearson Chi-squared
test and Fisher's Exact Test for Count Data (R Studio) were used for statistical analysis. Results of additional cadaver
work (with commercially available fillers) were compared and then included in the statistical analysis.

46 chapter 3 47
 methods
Frontal Concavity, Sharp Needle Technique Frontal Concavity, Non-Traumatic Cannula Technique

The needle was directly advanced to the periosteum of the frontal bone, perpendicular to the skin. With the tip of the The cannula was introduced from the temporal crest through an opening in the skin that was made with a 23G
needle in direct and constant contact with the periosteum, a bolus of approximately 0.1 ml was slowly injected. The needle. The skin and muscle in front of the cannula were elevated to create a path of least resistance toward the deep
needle was then withdrawn and reintroduced approximately 1 cm further along where additional injections of the anatomical layers. To pass the resistance of the galea aponeurotica, the cannula was rotated with a fast rotation of the
same volume were injected in the same manner, totaling approximately 0.5 ml (Figure 1A and 1B). syringe between the fingers of the injector (rotating technique). After passing this resistance, the injector assumed that
the cannula was placed in the glide space between the periosteum and the galea and advanced the cannula at the
subgaleal level. Multiple small deposits totaling approximately 0.5 ml were injected in a retrograde fanning technique
and lightly massaged after injection (Figure 2A and 2B).
Frontal concavity, sharp needle
Perpendicular, bolus technique

Frontal concavity, blunt cannula

Oblique, retrograde technique

Figure 2
Frontal concavity injected with blunt cannula demonstrated on an 85-year-old male cadaver. A: Schematic
diagram of supraperiosteal injection technique. The 25G blunt cannula was advanced directly to the
periosteum through a pre-hole in the skin that was made with a 23G needle at the temporal crest. The
Figure 1 cannula was then obliquely advanced through the skin, the galea aponeurotica and the frontalis muscle
Frontal concavity injected with sharp needle demonstrated on an 85-year-old male cadaver. A: Schematic to the glide space over the periosteum. Multiple retrograde linear threads of yellow dye were injected on
diagram of supraperiosteal injection technique. The 25G sharp needle was advanced directly to the the periosteum in a fanning pattern. A total of approximately 0.5 mL was injected at that level. B: Overview
periosteum perpendicular to the skin. Multiple boluses were injected with the needle in constant contact image of cadaver injection. C: Subcutaneous view (skin resected). No dye was observed at this level.
with the periosteum. A total of approximately 0.5 mL yellow dye was injected at that level. B: Overview image D: Periosteal view (frontalis muscle everted). Dye (yellow) is placed more evenly and is mostly confined to
of cadaver injection. C: Subcutaneous view (skin resected). Note the presence of dye (yellow) superficially. the glide space between the periosteum and the galea aponeurotica. One small deposit of yellow dye was
D: Periosteal view (frontalis muscle everted). Note the lumpy appearance of the yellow dye and the found in the submuscular layer, no dye was found intramuscularly or more superficially. (Green dye was
accidental intra-vascular injection in the supraorbital artery (white arrow). used for other observations that are not relevant to this study).

48 chapter 3 49
 methods
Temporal Hollows, Sharp Needle Technique Temporal Hollows, Non-Traumatic Cannula Technique

The needle was advanced directly to the periosteum of the temporal area at the point of maximum depression, The cannula was introduced from the lateral side of the temporal crest through an opening in the skin and both
perpendicular to the skin. With the needle tip touching the periosteum, small boluses of approximately 0.1 ml were temporal fascias made with a 20G needle. After passing the fascia, the injector assumed that the cannula was
injected with low pressure. After injection of one bolus, the needle was partly retracted, without exiting the skin, positioned at the periosteum and advanced the cannula at the submuscular level. Small, retrograde, linear threads
reoriented and readvanced to the periosteum, approximately 5 mm away from the previous injection site. The total totaling approximately 0.5 ml were then injected using a fanning technique followed by light massage (Figure 4A
volume injected was approximately 0.5 ml (Figure 3A and 3B). and 4B).

Temporal hollows, sharp needle Temporal hollows, blunt cannula

Perpendicular, bolus technique Oblique, retrograde technique

Figure 4
Temporal hollow injected with blunt cannula demonstrated on a 93-year-old female cadaver.
Figure 3 A: Schematic diagram of supraperiosteal injection technique. The 25G blunt cannula was advanced
Temporal hollow injected with sharp needle demonstrated on an 85-year-old male cadaver. A: Schematic directly to the periosteum through a pre-hole in both the skin and the deep temporal fascia that was made
diagram of supraperiosteal injection technique. The 25G sharp needle was advanced directly to the with a 20G needle just lateral to the temporal crest. The cannula was then obliquely advanced through
periosteum perpendicular to the skin. Multiple boluses were injected with the needle in constant contact the skin, the deep temporal fascia and the temporalis muscle to the periosteum. Multiple retrograde linear
with the periosteum. A total of approximately 0.5 mL yellow dye was injected at that level. B: Overview image threads were injected on the periosteum in a fanning pattern. A total of approximately 0.5 mL yellow dye
of cadaver injection. C: View of the deep temporal fat (skin and superficial fascia everted). No yellow dye was injected at that level. B: Overview image of cadaver injection. C: Subcutaneous view (skin resected).
was observed at this depth (green and red colored dyes were injected at more superficial levels and are not No dye was observed at this level or in the deep temporal fat pad. D: Periosteal view (temporal muscle
the subject of this study). D: Periosteal view (temporal muscle everted). Almost all yellow dye was located everted). Dye (yellow) is placed more evenly and is mostly confined to the periosteum. Small deposits were
intramuscularly. (Green and red dyes were used for other observations and are not relevant to this study). found intramuscularly.

50 chapter 3 51
 methods
Temporal Hollow, Long Sharp Needle Oblique Technique Tear Trough, Sharp Needle Technique

To assess the possibility that the difference between needle and cannula observations was due to the angle under The tear trough was marked between the infraorbital rim and the infraorbital foramen and the needle advanced
which the cannula moves through the tissue (oblique vs. perpendicular to the skin), we also injected one cadaver in perpendicular to the skin directly to the periosteum of the tear trough. Small aliquots of dye were injected with the
the temporal hollow with a long sharp needle (27G, 40mm), using the same trajectory as in the cannula technique. needle in constant contact with the periosteum. In between aliquots, the needle was “walked” over the periosteum a
The 27G (40mm) sharp needle was advanced directly to the periosteum with an oblique angle to the skin. As soon as few millimeters adjacent to where the first bolus was injected. In this manner, multiple, small deposits of dye were
the needle tip made contact with the periosteum, the needle was advanced over the periosteum. Multiple retrograde injected. The skin was penetrated a total of 4 times, and 8 small boluses of approximately 0.05 ml were deposited
linear threads were injected with the needle in constant contact with the periosteum. A total of approximately 0.3 ml (Figure 6A and 6B).
(yellow dye) was injected at this level (Figure 5 A and B).

Figure 5
Temporal hollow injected with long sharp needle demonstrated on an 85-year-old male cadaver.
A: Schematic diagram of supraperiosteal injection technique. The 27G (40 mm) sharp needle was Figure 6
advanced directly to the periosteum at an oblique angleto the skin. As soon as the needle tip was in contact Tear trough injected with sharp needle demonstrated on a 93-year-old female cadaver.
with the periosteum, the needle was advanced over the periosteum. Multiple retrograde linear threads were A: Schematic diagram of supraperiosteal injection technique. The 25G sharp needle was advanced directly
injected with the needle in constant contact with the periosteum. A total of approximately 0.3 mL yellow dye to the periosteum perpendicular to the skin. Multiple boluses were injected with the needle in constant
was injected at that level. B: Overview image of cadaver injection. C: View of the deep temporal fat (skin and contact with the periosteum. A total of approximately 0.2 mL yellow dye was injected at that level. B:
superficial fascia everted). No yellow dye was observed at this depth (green colored dye is not the subject Overview image of cadaver injection. C: Subcutaneous view (skin resected). Note the presence of yellow
of this study). D: Periosteal view (temporalis muscle everted). Most dye (yellow) was found located on the dye at this superficial level. D: Periosteal view (orbicularis oculi muscle everted). Dye (yellow) was found in all
periosteum with small amounts intramuscularly. layers; on the periosteum, intramuscularly and subcutaneously in contact with the skin.

52 chapter 3 53
 methods
Tear Trough, Non-Traumatic Cannula Technique Lateral Mandible, Sharp Needle Technique

The cannula was introduced through the skin just lateral to the point where the nasojugal groove crosses the alar- A 27G, 40 mm long needle was inserted perpendicular to the skin and advanced directly to the periosteum of the
tragal line. It was then advanced obliquely through the skin and the superficial musculo aponeurotic system (SMAS), mandible, medial and cranial to the mandibular angle, deep to the masseter muscle. With the needle tip touching the
directly to the periosteum of the tear trough, where retrograde linear threads were injected. A total of approximately periosteum, small boluses of approximately 0.1 ml yellow dye were injected with low pressure. After injection of 1
0.2 ml was injected (Figure 7A and 7B). bolus, the needle was partly retracted, without exiting the skin, reoriented and readvanced to the periosteum,
approximately 5 mm away from the previous injection site. A total volume of approximately 0.5 ml was injected
(Figure 8A and 8B).

Figure 7 Figure 8
Tear trough injected with blunt cannula demonstrated on a 93-year-old female cadaver. A: Schematic Mandibular angle injected with sharp needle demonstrated on an 85-year-old male cadaver.
diagram of supraperiosteal injection technique. The 25G blunt cannula was advanced directly to the A: Schematic diagram of supraperiosteal injection technique. The 27G, 40 mm long sharp needle was
periosteum through a pre-hole in the skin that was made with a 23G needle lateral to the skin insertion advanced directly to the periosteum perpendicular to the skin. Multiple boluses were injected with the
of the zygomatico cutaneous ligament. The cannula was then obliquely advanced through the skin and needle in constant contact with the periosteum. A total of approximately 0.5 mL (yellow dye) was injected at
the superficial musculo-aponeurotic system to the periosteum. Multiple retrograde linear threads were that level. B: Overview image of cadaver injection. C: Subcutaneous view (skin resected). Note the presence
injected on the periosteum in a fanning pattern. A total of approximately 0.2 mL yellow dye was injected of yellow dye at this level. D: Periosteal view (masseter muscle is incised). Dye (yellow) was found mostly
at that level. B: Overview image of cadaver injection. C: Subcutaneous view (skin resected). No dye was intramuscularly. Note the proximity of the facial artery (dyed red) to the injected product (white arrow).
observed at this level. D: Periosteal view. Dye (yellow) was found on the periosteum. (Green dye were used for other observations that are not relevant to this study).

54 chapter 3 55
 methods
Lateral Mandible, Non-Traumatic Cannula Technique Mentum, Non-Traumatic Cannula Technique

The cannula was inserted through an opening in the skin at the mandibular angle and advanced directly to the The cannula was inserted through an opening in the skin at the pre-jowl sulcus and advanced directly to the
periosteum of the mandible, manoeuvring through the resistance of the SMAS and the tendinous attachments of the periosteum of the mentum, manoeuvering through any resistance using the rotating technique. Retrograde linear
masseter to the mandible using the rotating technique. Retrograde linear threads of green dye were injected with the threads were placed at the periosteal level under the mentalis muscle in retrograde linear threads for a total volume of
cannula moving over the periosteum for a total volume of approximately 0.5 ml (Figure 9A and 9B). approximately 0.3 ml (Figure 10 A and 10B).

Figure 10
Figure 9 Mentum injected with blunt cannula demonstrated on an 85-year-old male cadaver. A: Schematic diagram
Mandibular angle injected with blunt cannula demonstrated on a 93-year-old female cadaver. A: Schematic of supraperiosteal injection technique. The 25G blunt cannula was advanced directly to the periosteum
diagram of supraperiosteal injection technique. The 25G blunt cannula was advanced directly to the through a pre-hole in the skin that was made with a 23G needle at the pre-jowl sulcus. The cannula was
periosteum through a pre-hole in the skin that was made with a 23G needle at the mandibular angle. The then obliquely advanced through the skin, advanced through the depressor labii inferioris muscle to the
cannula was then obliquely advanced through the skin, advanced through the SMAS and the adhesions of periosteum of the mandible and then advanced underneath the mentalis muscle. Multiple retrograde linear
the masseter to the mandible down to the periosteum. Multiple retrograde linear threads were injected on threads were injected on the periosteum in a fanning pattern. A total of approximately 0.3 mL was injected
the periosteum in a fanning pattern. A total of approximately 0.5 mL green dye was injected at that level. B: at that level. B: Overview image of cadaver injection. C: No yellow dye was observed in the subcutaneous or
Overview image of cadaver injection. C: Subcutaneous view (skin resected). No dye was observed at this muscular levels. D: Periosteal view. Dye (yellow) was exclusively found on the periosteum (green dye in this
level. D: Periosteal view. Dye (green) was mostly found on the periosteum and some intramuscularly. image was used for more superficial injection and is not the subject of this study).

56 chapter 3 57
 methods
Mentum, Sharp Needle Technique Additional Cadaver Dissections

The needle was inserted perpendicular to the skin and advanced directly to the periosteum of the mentum, just lateral Four and eight months after the two initial cadaver dissections had taken place, two of the authors (JvL and DH)
to the midline, below the mentalis muscle. With the needle tip in constant contact with the periosteum, small boluses performed additional cadaver dissections on two unembalmed cadaver heads (both female, 81 and 78 years old
of approximately 0.1 ml were injected with low pressure. After injection of a bolus, the needle was partly retracted, respectively). The second series of dissections used the same needle and cannula injection techniques as before, but
without exiting the skin, reoriented and readvanced to the periosteum, approximately 5 mm away from the previous injected commercially available fillers. Approval to take photographs in the cadaver lab was not available. The fillers
injection site. A total volume of approximately 0.3 ml was injected (Figure 11 A and B). were supplied by Merz Aesthetics GmBH (Frankfurt am Main, Germany). The 1 ml syringes of hyaluronic acid (HA)
products were mixed with 0.05 ml dye. Calcium hydroxylapatite (CaHA) did not require the addition of a dye because
of its existing white color. The following allocation was used for the supraperiosteal placement of the different
products: frontal concavity: HA (Belotero Intense); temporal hollows: CaHA (Radiesse); tear troughs: HA (Belotero
Balance); mandible: CaHA (Radiesse) and mentum: CaHA (Radiesse). The two authors recorded their findings
(Table 1).

Table 1
Possible Factors Influencing Spread Among Tissue Layers

Tissue Cadaver tissue vs live tissue

properties
• No muscle tonus in cadavers might increase spread

• Time wasting resulting in friable tissue and increased spread

• Freezing and thawing might damage tissues and increase spread

Age of the patient/cadaver: older age may have increased spread due to less dense aged tissues

Different anatomical layers may have different resistance to product and thereby influence spread:

• Periosteum (dense)

• Fat (loose)

• Muscle (loose along fibers) • Fascias (dense)

• Dermis (dense)

Continued on next page

Figure 11
Mentum injected with sharp needle demonstrated on an 85-year-old male cadaver. A: Schematic diagram
of supraperiosteal injection technique. The 25G sharp needle was advanced directly to the periosteum
perpendicular to the skin. Multiple boluses were injected with the needle in constant contact with the
periosteum. A total of approximately 0.3 mL (red dye) was injected at that level. B: Overview image of
cadaver injection. C: Red dye was observed inside the mentalis muscle. D: Periosteal view. Dye (red) was
found mostly intramuscularly and some on the periosteum. Note the difference between yellow (cannula)
and red (needle) placement of dye (green dye in this image was used for more superficial injection and is not
the subject of this study).

58 chapter 3 59
 methods
Fifty-eight expert injectors were included in the online poll of whom 77% were aesthetic physicians, 15%
Tissue Cadaver tissue vs live tissue dermatologists, and 2% plastic surgeons. Needles were thought to be more precise for placing a filler at the
properties periosteum by 79% of consulted physicians, whereas 21% believed cannulas were more precise; 71% of the consulted
• No muscle tonus in cadavers might increase spread experts agreed that cannulas are safer than needles for injecting fillers at the periosteum. Most experts (79%) used a
perpendicular approach when using sharp needles to place fillers on the periosteum, whereas an oblique approach
• Time wasting resulting in friable tissue and increased spread was used by 76% of experts when using non-traumatic cannulas to place fillers on the periosteum.

• Freezing and thawing might damage tissues and increase spread In the initial cadaver dissections all facial sites consistently showed that the sharp needle technique with the needle
perpendicular to the skin, resulted in product being placed at multiple anatomic layers, from the periosteum to
Age of the patient/cadaver: older age may have increased spread due to less dense aged tissues more superficial layers, and occasionally ending up at the subdermal and dermal levels. The non-traumatic cannula
technique resulted in product being confined to significantly fewer anatomic layers (Table 1).
Different anatomical layers may have different resistance to product and thereby influence spread:

• Periosteum (dense) Frontal Concavity, Sharp Needle Technique

• Fat (loose) When the skin was dissected, dye was observed in the subcutaneous fat (Figure 1C) in contact with the skin.
When the frontalis muscle was resected, product was found intramuscularly, in the galea aponeurotica and on the
• Muscle (loose along fibers) • Fascias (dense) periosteum (Figure 1D). It was noted that the product was placed unevenly. Of greater concern was that even though
the needle tip had been in constant contact with the periosteum on injection, intravascular injection of the lateral
• Dermis (dense) branch of the supraorbital artery had occurred (Figure 1D, white arrow).

Technique Angled approach vs perpendicular approach

specifics
• Needle and cannula trajectories represent possible paths of least resistance

• When the path of least resistance traverses multiple anatomical layers, the chance of backflow to these
layers increases

Lumen of the needle/cannula might influence backflow

Applied pressure to the syringe might influence backflow positively

• Fat (loose)

• Muscle (loose along fibers)

• Fascias (dense)

• Dermis (dense)

Product Rheologic properties influence the amount of spread in the tissue

properties
• Viscosity

• Elasticity

• Cohesivity

Other product-related factors • Particle size

• Concentration of HA/hydration • Crosslinking

• Temperature

60 chapter 3 61
 results
Frontal Concavity, Non-Traumatic Cannula Technique

On dissection, almost all of the injected dye was found to be confined to the submuscular level. No product was
found intramuscularly or subcutaneously (Figure 2C). Most dye was placed at the periosteum and a small deposit was
found inside the galea aponeurotica sub-muscular plane, just deep to the frontalis muscle (Figure 2D). Compared to
the sharp needle technique, the dye was placed more evenly.

Temporal Hollows, Sharp Needle Technique

On dissection, no dye was observed subcutaneously or in the deep temporal fat compartment. Most of the dye was
observed intramuscularly. Almost no product was observed on the periosteum (Figure 3D).

Temporal Hollows, Non-Traumatic Cannula Technique

On dissection, most of the injected dye was confined to the supraperiosteal, submuscular level. A small amount
appeared to be located in the temporalis muscle. No dye was found superficial to the deep part of the muscle (Figure
4C). Compared to the sharp needle technique, the dye was placed more evenly (Figure 4D).

Temporal Hollows, Long Sharp Needle, Oblique Retrograde Technique

On dissection, no dye was observed in superficial layers (Figure 5C). Most of the injected dye was found on the
periosteum with a few deposits intramuscularly (Figure 5D).

Tear Trough, Sharp Needle Technique

Figure 12 On dissection, dye was seen in contact with the skin, in the subcutaneous level, in the orbicularis oculi muscle and on
Mode of Action. Arterial embolism after sharp needle injection the periosteum (Figure 6C and 6D).
Proposed mechanism of action for the accidental intra-arterial injection that was observed after sharp
needle injection in the frontal area. As the needle is advanced to the periosteum, it hits the artery, pushing
it down to the bone. At that level, the bevel of the needle penetrates the arterial wall so that the lumen of the Tear Trough, Non-Traumatic Cannula Technique
needle is in contact with the lumen of the artery. On injection, the dye was injected into the lumen of the artery.
On dissection, product was seen in contact with the periosteum and not in any other anatomic layer (Figure 7C
and 7D).

Lateral Mandible, Sharp Needle Technique

On dissection, product was observed intramuscularly. Almost no product was observed submuscularly and a minimal
amount of dye was observed superficial to the muscle (Figure 8C and 8D)

Lateral Mandible, Non-Traumatic Cannula Technique

On dissection, product was mostly observed in the submuscular plane on the periosteum of the mandible with a small
amount injected intramuscularly (Figure 9C and D).

62 chapter 3 63
 discussion
Aesthetic medicine is a relatively young medical field and the available scientific evidence is limited. Best practice
Mentum, Non-Traumatic Cannula Technique techniques are generally learnt from peers at expert meetings and congresses. The introduction and adoption of
cannulas to deliver soft-tissue fillers has led to a debate on the use of cannulas over sharp needles.19 Previously, it had
On dissection, product was observed exclusively in the submuscular, supraperiosteal plane (Figure 10C and 10D, been assumed that the supraperiosteal placement of fillers with a sharp needle was a very precise technique, because
yellow dye). of the exact placement of the needle tip. This assumption still represents the majority view, as shown from our poll of
expert injectors.

Mentum, Sharp Needle Technique In this observational, cadaver dissection study, we found that the sharp needle technique for periosteal injection of
fillers, resulted in product placement not only in the supra-periosteal layer, as was expected, but also in additional
On dissection, product was observed intramuscularly. Almost no product was observed submuscularly (Figure 11C anatomic layers, sometimes even as superficial as the subdermis and dermis. The difference in accuracy of filler
and 11D, red dye). placement at the preperiosteal level by sharp needles or blunt cannulas can be influenced by multiple factors as
summarized in Table 1. We postulate that the most likely reason for the increased product spread with needles is that
the material had flowed backward in a retrograde direction through the track of the needle, following the path of
Additional Cadaver Dissections least resistance. The needle had been placed on the periosteum via a direct approach perpendicular to the skin, as is
common practice, in order to minimize sharp needle associated risks such as bruising and intravascular injection. The
Comparable results were observed when 2 additional cadaver heads were injected with commercially available sharp needle with its beveled point is able to puncture soft tissue layers. However, when the needle tip encounters a
fillers and dissected. There was no statistical difference in results between the dye and filler dissections. In all the hard surface such as bone, the bevel is unlikely to completely penetrate the penultimate layer (e.g. epi-mysium) and
cadaver dissections, the cannula technique consistently resulted in product in fewer anatomic layers than the needle the product is then injected into the muscle body rather than the supra-periosteal layer; this was a consistent finding
technique. The results of these observations were scored and used for statistical analysis (Supplementary Figure 1). in all the areas studied.

To avoid retrograde flow to more superficial layers in clinical practice, an angled instead of perpendicular approach
could be considered, as was demonstrated with the long, sharp needle using an oblique pathway. While such an
approach may result in limited product flow to the superficial anatomic layers in vivo, it would pose increased needle-
associated risks. In this study, we have established that when a needle was used in an oblique fashion, precision of
placement on the periosteum of the temporal hollow was similar to a cannula. However, oblique needle injection
might pose more complication risks, as the sharp tip of the needle has a longer path through the tissue, increasing the
possibility of the sharp tip damaging an anatomic structure in its trajectory. Theoretically, a perpendicular cannula
approach could result in similar results to that seen with needles. We hypothesize that perpendicular use of cannulas
will result in even less precise product placement on the periosteum, as the opening of the cannula is not located
at the tip, but about 1-2 mm proximal to the tip on the side of the cannula. Even if the cannula tip is placed on the
periosteum, the filler will be expressed more superficially, potentially not reaching the periosteal level. Perpendicular
use of cannulas was not reported by any of the expert injectors that contributed to the poll. The possible bias due
to angle of approach is therefore more a theoretical discussion point than a practical one, as in clinical practice
the cannula is generally used obliquely and the needle is generally used perpendicularly when injecting on
the periosteum.

In clinical practice, hydro-dissection with saline or a local anaesthetic could be considered at the pre-periosteal level
to reduce tissue resistance to the filler and therefore limit backflow through the needle trajectory. The disadvantage
of this approach is that the injected volume of saline or local anaesthetic will influence the aesthetic baseline prior
to injection of filler product. In addition, dilution of filler with saline or lidocaine might alter the rheologic properties
of the injected product. If a practitioner chooses the sharp needle technique for supraperiosteal injection, the depot
technique as described by G. Sattler is recommended.20 With this approach, the tissue is lifted with the non-injecting
hand during injection thereby increasing the pressure and thus the resistance in the superficial anatomical layers by
the force of the pinching fingers. The technique may therefore be associated with less backflow to the superficial
layers, as product will always flow in the direction of least resistance.

The problem of inaccurate filler placement after hyaluronic acid injection at the periosteum with a sharp needle
technique has also been reported by Griepentrog et al.21 They demonstrated histologically that a significant amount
of hyaluronic acid gel (Juvéderm, Allergan, Inc.) did not end up in the intended periosteal plane when injected with
a needle in the infra-orbital hollow. Spread of gel to more superficial layers along the needle trajectory might be the
reason that malar edema is sometimes seen after needle injection of hyaluronic acid fillers.1

64 chapter 3 65
 discussion
In this study, the use of non-traumatic cannulas resulted in a more precise placement of injected material. The Statistically, this study could be described as a possible low powered study, because of the low number of included
dissection results showed the presence of injected product at the targeted supra-periosteal layer with only limited cadavers (four). However, if we recalculate our model for an “IF this than THAT” principle whereby we define five
product in the more superficial layer adjacent to the periosteum. Although we can assume that there is also backflow facial areas from two cadavers, multiply by two for both type of injectable materials what were used (dye and fillers
of gel along the trajectory of the cannula, it is likely to be restricted to the same anatomical layer, the periosteum, were not statistically different) this gives us 20 observations per needle and cannula. With a total of 40 observations,
because of the oblique approach of the cannula. this study shows us a positive and significant result in favor of the blunt cannula.

One drawback of the initial cadaver study is that we used colored acrylic dye to inject, and not commercial fillers.
Additional cadaver heads were therefore injected with commercially available fillers to determine whether there
were any differences in results based on the rheology of the specific products. Individual gels differ sufficiently in
their physical and chemical properties to influence their clinical performance. Rheologic properties relevant to the
performance of fillers include the degree of cross-linking (in case of hyaluronic acid), cohesivity (the tendency of a
gel to stick together and hold its form or shape under stress), gel hardness (G’), gel consistency, viscosity, extrusion
force, concentration, and extent of hydration. Differences in the rheologic properties of filler products reflect their
specific manufacturing processes and resultant physicochemical characteristics and influence their tissue spread
and postulated backflow along the needle trajectory.22 Two of the authors therefore performed additional cadaver
dissections using commercially available fillers. Results were very similar to the initial cadaver study with no statistical
difference between acrylic dye and commercial fillers. This may be explained by the fact that the disections were
performed immediately after injection leaving very little time for the dye to spread. The anatomy of the facial
area injected appears to be the defining factor along with the instruments (needle or cannula) and techniques
(perpendicular and oblique pathways) used. Other cadaver studies have shown that tissue spread differs with injected
substance. For example, CaHA was shown to be confined to the premaxillary space due to its high visco-elastic
properties, while a more fluid material spread beyond this semi-open space.23 Our findings may therefore not be
applicable to all filler substances. The diversity of the many filler products on the market with their different rheologic
characteristics makes it impossible to give a general conclusion about the extent of retrograde backflow through the
needle trajectory, except that a certain amount of backflow is possible. With a perpendicular approach this could
mean that the filler may present in multiple anatomic layers.

Our study had several limitations. We used fresh, frozen cadaver heads, and not fresh cadavers. The thawing of the Skin
Subcutanteous
frozen tissues could have adversely affected the normal fascial structures that, in vivo, act as effective barriers. Fresh, Musculo aponeurotic
Retaining Ligments and Spaces
frozen cadaver tissue represents a close enough proxy with respect to diffusion and dispersion of drugs, and it was Periosteum and deep fascia
Bone
therefore assumed that the tissue would be a realistic alternative to the in vivo situation as has been established by
other workers.24 The age of the cadavers (85 and 92 years) was not representative of the usual patients requesting Figure 13
filler treatments. Facial anatomy is known to significantly change with age, and most clinical patients are probably Proposed mechanism of backflow through the trajectory that was made with the sharp needle in a
in their fourth to sixth decades of life. Future studies with younger cadavers might yield different results. Cadavers perpendicular direction to the skin and with a blunt cannula that was advanced to the deep layers
have no muscle tonus and therefore we have to accept the possibility that in vivo, there may be a reduced chance with an oblique angle. The injected substance will follow the path of least resistance and therefore it is
of retrograde flow along the needle trajectory. In this study, we only injected with 25G and 27G needles, and 25G expected to flow back through the trajectory made by the needle or cannula. The needle spans multiple
cannulas. Even though the outer diameter of the needles and cannulas were known, the lumen diameters were anatomical layers over a shorter distance than the cannula distance and therefore it is expected that with
unknown. And therefor, the comparability of the two instruments might be reduced. We however believe that the a perpendicular approach, the injected substance will be deposited into more anatomical layers than with
lumen of the needles and cannulas used in this study are of less significance compared to the angle of the approach, a cannula. Note that the cannula technique entails an initial angled descent to the periosteum followed by
as the expressed product will follow the path of least resistance irrespective of the lumen of the needle or cannula. more horizontal advancement of the cannula at depth (illustrated by the bent tissue layer).
In common practice, a range of different sized needles and cannulas are used in multiple facial indications. Additional
studies might show a difference in results if different gauge needles or cannulas are used.

An important finding was that the lateral branch of the supraorbital artery (deep to the frontalis muscle) was
accidentally embolized on injection with the sharp needle technique. The tip of the needle was touching the
periosteum during the entire injection and therefore, this study demonstrates that periosteal placement of fillers with
a sharp needle can still result in inadvertent intravascular injection. We hypothesize that the anterior wall of the
artery was penetrated by the needle and the artery then pushed against the bone. In this position, the beveled sharp-
needle tip would be unable to penetrate the posterior wall of the artery as the needle will not advance into bone and
intravascular injection occurred. This possibility should therefore be considered when injecting with a sharp needle
on the periosteum (Figure 12).

66 chapter 3 67
 conclusions references
A consistent finding in this observational study was that the sharp needle injection technique with a perpendicular 1. Funt D, Pavicic T. Dermal fillers in aesthetics: an overview 13. Grunebaum LD, Allemann, IB, Dayan S, Mandy S,
approach resulted in dispersal of product into multiple anatomic layers and inconsistent placement in the supra- of adverse events and treatment approaches. Clin Cosmet Baumann L. The risk of alar necrosis associated with
periosteal layer. The cannula technique with an angled approach was a more accurate method of placing product in Investig Dermatol. 2013;6:295–316. dermal filler injection. Dermatol Surg. 2009;35:1635–
the supra-periosteal layer and may be considered a safer procedure. 2. Beer K, Beer J. Overview of facial aging. Facial Plast Surg. 1640.
2009;25:281–284. 14. Tansatit T, Apinuntrum P, Phetudom T. A cadaveric
The same findings were observed in all facial indications studied. The results suggest that using an oblique, angled 3. American Society for Aesthetic Plastic Surgery. Cosmetic feasibility study of the intraorbital cannula injections of
approach with non-traumatic cannulas results in more precise product placement when targeting a specific anatomic surgery statistics 2015. Available from: http://www. hyaluronidase for initial salvation of the ophthalmic artery
layer with a lower risk of complications. surgery.org/sites/default/files/Stats2015.pdf. Accessed 24 occlusion. Aesthetic Plast Surg. 2015;39:252–261.
April, 2016. 15. Kim DW, Yoon ES, Ji YH, Park SH, Lee BI, Dhong ES.
When injecting with a sharp needle and perpendicular approach, backflow to more superficial anatomic layers 4. Van Loghem J, Yutskovskaya Y, Werschler P. Calcium Vascular complications of hyaluronic acid fillers and the
was observed, probably as a result of flow of injected material along the perpendicular needle track as depicted in hydroxylapatite: over a decade of clinical experience. J role of hyaluronidase in management. J Plast Reconstr
Figure 13. However, additional variables that could influence the outcome of this observational study are possible as Clin Aesthet Dermatol. 2014;7:38-49. Aesthet Surg. 2011;64:1590-1595.
summarized in Table 1. To determine whether our observations reflect the in vivo situation, further cadaver studies are 5. Muhn C, Rosen N, Solish N, Bertucci V, Lupin M, 16. Zeichner JA, Cohen JL. Use of blunt tipped cannulas for
warranted with more specimens, using a range of commercially available filler products, different angled approaches, Dansereau N, Weksberg F, Kent Remington B, Swift soft tissue fillers. J Drugs Dermatol. 2012;11:70-72.
and different gauge needles and cannulas. Ultimately, a larger cohort is needed, in vivo, to make any kind of final A. The evolving role of hyaluronic acid fillers for facial 17. Fulton J, Caperton C, Weinkle S, Dewandre L. Filler
conclusions regarding the safety, precision, or amount of backflow of cannulas and needles. volume restoration and contouring: a Canadian overview. injections with the blunt-tip microcannula. J Drugs
Clin Cosmet Investig Dermatol. 2012;5:147–158. Dermatol. 2012;11:1098-1103.
Finally, a very important conclusion that can be made based on the results of this observational study is that injecting 6. Gierloff M, Strohring C, Buder, T, Gassling V, Acil Y, 18. Funt D. Avoiding malar edema during midface/cheek
with a sharp needle can potentially result in intravascular embolization, even when the needle is in constant contact Wiltfang J. Aging changes of the midface compartments: augmentation with dermal fillers. J Clin Aesthet Dermatol.
with the periosteum (Figure 1D (white arrow) and Figure 12). Safety is improved when injecting on the periosteum a computed tomographic study. Plast Reconstr Surg. 2011;4:32–36.
with non-traumatic cannulas, but not guaranteed. 2012;129:263–273. 19. Casabona G. Blood aspiration test for cosmetic fillers
7. Warren RJ, Aston SJ, Mendelson BC. Face lift. Plast to prevent accidental intravascular injection in the face.
Reconstr Surg. 2011;128:747e-764e. Dermatol Surg. 2015;41:841–847.
8. Sadick NS, Manhas-Bhutani S, Krueger N. A novel 20. Pavicic T. Complete biodegradable nature of calcium
approach to structural facial volume replacement. hydroxylapatite after injection for malar enhancement: an
Aesthetic Plast Surg. 2013;37:266–276. MRI study. Clin Cosmet Investig Dermatol. 2015;8:19-25.
9. Greco TM, Antunes MB, Yellin SA. Injectable fillers for 21. 21. Griepentrog GJ, Lemke BN, Burkat CN, Rose JG,
volume replacement in the aging face. Facial Plast Surg. Lucarelli MJ. Anatomical position of hyaluronic acid gel
2012;28:8–20. following injection to the infraorbital hollows. Opthal Plast
10. Gierloff M, Stöhring C, Buder T, Wiltfang J. The Reconstr Surg. 2013;29:35-39.
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Aesthet Surg. 2012;65:1292-1297. to aesthetic applications. Plast Reconstr Surg.
11. Lambros V. Observations on periorbital and midface 2013;132:5S-21S.
aging. Plast Reconstr Surg. 2007;120:1367–1376. 23. Pilsl U, Rosmarin W, Anderhuber F. The premaxillary
12. Sykes JM, Cotofana S, Trevidic P, Solish N, Carruthers J, space: a location for filler injection? Dermatol Surg.
Carruthers A, Moradi A, Swift A, Massry GG, Lambros V, 2014;40:301–304.
Remington BK. Upper face: clinical anatomy and regional 24. Batheja P, Sheihet L, Kohn J, Singer AJ, Michniak-Kohn
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2015;136:204S-218S. Formulation optimization and in vitro and in vivo skin
distribution studies. J Control Release. 2011;149:159-67.

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 supplementary data
This article contains supplementary material located online at www.aestheticsurgeryjournal.com. B

Supplementary Figure 1 Sharp needle

A
Blunt cannula

6
DYE Sharp needle Blunt cannula COMMERCIAL FILLERS Sharp needle Blunt cannula
5
Frontal concavity
4
Skin Skin
Subcutaneous fat Subcutaneous fat 3
Frontalis muscle Frontalis muscle
Galea aponeurotica Galea aponeurotica 2
Subgaleal space Subgaleal space
Periosteum Periosteum 1

Temporal Hollows
0
Skin Skin Frontal Temporal Tear Mandibular Mentum
Subcutaneous fat Subcutaneous fat concavity hollows troughs angle
Temporoparietal fascia Temporoparietal fascia
A: Anatomical layers in contact with dye and commercial fillers. The two authors reported whether the dye
Deep temporal fat compartment Deep temporal fat compartment
(left) or commercial filler (right) was in contact with the corresponding anatomical layer (horizontal rows)
Deep temporal fascia Deep temporal fascia
after periosteal injection with a sharp needle (perpendicular approach) or blunt cannula (oblique approach).
Temporalis muscle Temporalis muscle
Blue boxes: both cadaver specimens had positive results. Grey boxes: one of the two cadaver specimens
Periosteum Periosteum
positive results. White boxes: none of the cadaver specimens had positive results.
Tear Troughs B: Graphical representation of amount of anatomical layers in contact with dye and commercial filer
material following injection with sharp needle vs. blunt cannula.
Skin Skin
Subcutaneous fat Subcutaneous fat
SMAS/orbicularis SMAS/orbicularis
Medial SOOF Medial SOOF
Glide space Glide space
(Malar septum) (Malar septum)
Periosteum Periosteum

Mandibular Angle

Skin Skin
Subcutaneous fat Subcutaneous fat
SMAS SMAS
Premasseteric Space Premasseteric Space
Masseter Masseter
Periosteum Periosteum

Mentum

Skin Skin
Subcutaneous fat Subcutaneous fat
SMAS/mentalis SMAS/mentalis
Pre-periosteal fat Pre-periosteal fat
Periosterum Periosteum

70 chapter 3 71
 04
Sensitivity of Aspiration as
a Safety Test Before Injection
of Soft Tissue Fillers.

First author. Impact Factor 1.903, SJR 0.807

Published in Journal of Cosmetic Dermatology. 2018 Feb;17(1):39-46.

Van Loghem JAJ1,2, Fouché JJ2, Thuis J2.

1. Depertment of Ophthalmology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
2. UMA Institute private practice, Amsterdam, Netherlands

72 chapter 4 73
 summary
Background Results
Embolism due to accidental intra-arterial injection of a A total of 340 individual aspiration tests with different
soft tissue filler (STF) can lead to serious complications. STFs and needles were performed, of which 112 yielded
Physicians practice aspiration as a safety test before true-positive results within 1-s and 128 yielded false-
injection to rule out intra-arterial placement of the needle negative results after 10 s. Positive results between one
tip. The value of aspiration as a safety test is evaluated in and ten seconds were seen in 101 aspiration tests.
this study, which also considered the rheological properties
of different STFs and their needle dimensions. Conclusions
True-positive results were seen in 33% of the tests
Methods performed with STFs within 1 s of aspiration. Aspiration
Aspiration with eleven different needle sizes and 24 test results are influenced by needle diameter, needle
different STFs was performed using Ringer’s lactate (RL) length, and rheological properties of STFs. Additional safety
colored with blue skin marking ink and secondly an measures are necessary to further reduce risk of inadvertent
empty saline bag containing anticoagulated blood, both intravascular injection of STFs.
pressurized to 150 mm Hg to mimic arterial blood pressure.
Time between the start of aspiration and liquid in the needle Keywords
hub was recorded. aspiration, complications, embolism, prevention,
soft tissue fillers

74 chapter 4 75
 introduction methods
Botulinum toxin type A and soft tissue filler (STF) treatments are immensely popular, a major reason being the minimal To create an environment where we could be certain of mimicking an intravascular positioning of a needle tip, we first
amount of downtime experienced when compared to surgical aesthetic procedures. Over the past few years, there used a 500 mL bag of Ringer’s Lactate" (RL) (Baxter Healthcare Corporation, Deerfield, IL, USA) solution pressurized
has been a significant increase in the amount of injectable treatments performed. Nonpermanent STF treatments are to 150 mm Hg by means of a Metpak" pressure infusor (Riester GmbH, Jungingen, Germany) to which was added 2
second on the list of nonsurgical procedures performed in the United States (after botulinum toxin type A treatments), mL Bonnie’s Blue" (Delasco, Council Bluffs, IA, USA) skin marking ink. The appearance of a blue color in the needle
with 2.1 million hyaluronic acid procedures conducted in 2015.1 hub was considered as a positive aspiration test result (Figure 1). Eleven different sharp point needle sizes were tested
on all products as well as the needles that were supplied with the products by the manufacturer (Table 1).
Various complications after the use of STFs have been documented. Among these, the occurrence of an intra-arterial The syringes and STF products tested are listed in Table 2.
embolism due to accidental intravascular injection is among the most serious.2

After intra-arterial injection of gel-based substances, blood flow to a critical anatomic area may be restricted or Table 1
blocked, leading to ischemia, followed by necrosis and sometimes, permanent scarring and disfigurement or even Sharp point needle gauge and length of needles tested in the study
blindness.3-9 To avoid or limit this risk, many experts and pharmaceutical companies advocate performing aspiration
before injection, as blood in the hub of the needle during aspiration confirms an intravascular needle position, after Needle size Manufacturer (products with manufacturer supplied needles are indicated in brackets)
which injection should be avoided. When considering the rise in STF treatments, the incidence of complications is
likely to also increase. A critical review of current techniques and materials used is therefore imperative. 33G, 13 mm TSK Laboratory, Japan

Apart from needle diameter and length, extrusion and aspiration of STFs are dependent on differences in 30G, 13 mm TSK Laboratory, Japan
physiochemical structure and rheological properties. The elastic quantitative measurement (elasticity) of a STF’s
stiffness and its ability to resist deformation under applied pressure are known as G prime (G’).10 The higher the G’ of 30G, 12 mm Terumo Europe N.V. Belgium (Etermis)
a STF, the less it will deform under pressure and the more stored energy it retains. Thickness, or viscosity of a STF in
its fluid form (g*), refers to the measure of its resistance to gradual reformation by shear stress and how it flows from 29G, 12 mm Terumo Europe N.V. Belgium (Restylane)
the needle while being injected. Therefore, elasticity and viscosity will also determine how a STF product behaves
in the lumen of the needle when aspiration is applied. The higher the G’ and g*, the more force is needed to obtain 28G, 19 mm Exelint International, USA (Radiesse)
a positive aspiration result by emptying a needle filled with STF material. Most commercial STF products have a
viscosity between 7.307 centipoises (cP) (Juvederm Ultra", Allergan Inc., Irvine, CA, USA) and 349 830 cP (Radiesse", 27G, 12 mm Terumo Europe N.V. Belgium (Etermis)
Merz Pharmaceuticals GmbH, Frankfurt, Germany).11 When comparing these values to water (0.890 cP at 25°C) and
blood (between 3.000 and 4.000 cP at 37°C), it becomes clear that the results of an aspiration test may not always be 27G, 13 mm TSK Laboratory, Japan
reliable as the high viscosity of STFs would mean that a very high suction pressure must be applied in order to obtain
a positive aspiration test result.12 27G, 20 mm Terumo Europe N.V. Belgium (Radiesse Plus, Etermis)

Our aim of this study was to investigate the value and reliability of aspiration as a medical test to prevent mistakenly 25G, 13 mm TSK Laboratory, Japan
placing a product in a vascular structure leading to possible complications, while comparing different STFs and
needle dimensions. 25G, 25 mm Terumo Europe N.V. Belgium (Etermis)

23G, 13 mm TSK Laboratory, Japan

Table 2
Syringes and soft tissue fillers tested

Soft tissue filler Contents

Control (C) Saline in a 1 ml Norm-Ject Tuberkulin syringe (Henke Sass Wolf)

Belotero Hydro®, 21 mg/ml glycerol, 18 mg/ml hyaluronate

Belotero Soft® Plus 20 mg/ml HA containing 0.3% lidocaine

Belotero Balance® Plus 22.5 mg/ml HA containing 0.3% lidocaine

Continued on next page

76 chapter 4 77
 methods
All products except the control were produced and supplied by the respective pharmaceutical companies in the
Soft tissue filler Contents Netherlands. Belotero", Radiesse", and Etermis" products were supplied by Merz Pharmaceuticals, Restylane" products
were supplied by Galderma, and Juvederm" products were supplied by Allergan. Every product except the control
Belotero Intense® Plus 25 mg/ml HA containing 0.3% lidocaine was tested with its originally supplied syringes, all of which were 1-mL syringes, with the exception of Radiesse" which
was supplied with 1.5 and 0.8-mL syringes. Each product was aspirated twice with every needle size to determine
Belotero Volume® Plus 26 mg/ml HA containing 0.3% lidocaine whether any of the blue-dyed Ringer’s lactate could be aspirated. Before testing, the needles were primed and the
syringes emptied of half of their STF contents to allow for sufficient aspiration with the plunger. A minimum of 0.5
Undiluted Radiesse® 0.8 ml syringe CaHA mL vacuum was visible in the syringe when the plunger was pulled during aspiration, which correlates to a negative
pressure of 50 mm Hg or 6666.118 Pa.13 A timer was used to measure the time between start of aspiration and the
Diluted Radiesse® 0.8 ml syringe CaHA with 0.16 ml Xylocaine® 1% mixed according to the FDA approved protocol appearance of blue color in the needle hub. When STF product packages contained needles with dimensions other
than our selected needle dimensions, these needles were also tested with the STF’s with which they were supplied.
Undiluted Radiesse® 1.5 ml syringe CaHA The aspiration test was then repeated using the same protocol, but replacing the dyed lactate solution with blood
drawn from two of the authors (JvL and JF). Prior to use, the blood was anticoagulated using tubes containing
Diluted Radiesse® 1.5 ml syringe CaHA with 0.3 ml Xylocaine® 1% mixed according to the FDA approved protocol ethylenediaminetetraacetic acid (EDTA) with a concentration of 1.8 mg/mL of blood.

Radiesse Plus® 1.5 ml syringe CaHA containing 0.3% lidocaine

Etermis 2® 20 mg/ml HA

150 mmHG HA/CaHA

Etermis 3® 23 mg/ml HA

Etermis 4® 24 mg/ml HA

Juvéderm Volbella® 15 mg/ml HA containing 3 mg/mL lidocaine hydrochloride

1:
Juvéderm Volift® 17.5 mg/ml HA containing 3 mg/mL lidocaine hydrochloride

Juvéderm Voluma® 20 mg/ml HA containing 3 mg/mL lidocaine hydrochloride

Juvéderm Ultra 2® 24 mg/ml HA containing 3 mg/mL lidocaine hydrochloride

Juvéderm Ultra 3 24 mg/ml HA containing 3 mg/mL lidocaine hydrochloride

Juvéderm Ultra 4® 24 mg/ml HA containing 3 mg/mL lidocaine hydrochloride

Juvéderm Ultra Smile® 24 mg/ml HA containing 3 mg/mL lidocaine hydrochloride

Restylane Kysse® 20 mg/ml HA containing 3 mg/mL lidocaine hydrochloride

2:
Restylane Defyne® 20 mg/ml HA containing 3 mg/mL lidocaine hydrochloride

Restylane Refyne® 20 mg/ml HA containing 3 mg/mL lidocaine hydrochloride

Restylane Lyft® 20 mg/ml HA containing 3 mg/mL lidocaine hydrochloride

Restylane Lidocaine® 20 mg/ml HA containing 3 mg/mL lidocaine hydrochloride

Restylane Fynesse® 20 mg/ml HA containing 3 mg/mL lidocaine hydrochloride Figure 1

Two series of aspiration tests were performed; the first using Ringer’s lactate dyed with blue ink and
Restylane Volyme® 20 mg/ml HA containing 3 mg/mL lidocaine hydrochloride pressurized to 150 mm mercury to mimic arterial blood pressure. The second test was performed in
the same way, but with EDTA-anticoagulated blood that was pressurized to 150 mm mercury
CaHA: calcium hydroxylapatite. HA: hyaluronic acid.

78 chapter 4 79
 results
The aspiration results are shown in Table 3. All needles tested in the 12 saline control tests yielded positive results PRODUCT AGENT NEEDLE gauge (G), length
within 1 s of aspiration. In total, 340 tests with 24 STFs were performed; 112 tests yielded true-positive results (within 23, 19mm 25, 13mm 27, 13mm 28, 19mm 30, 13mm 33, 13mm
1 s), 101 tests yielded positive results between 1 and 10 s after aspiration, and 128 tests yielded negative results 13 mm
beyond 10 s of aspiration. RL + ink 3 sec.
12 mm
The reliability of aspiration as a safety test when a true-positive result was defined as being positive up to 10 s after the ETERMIS 3
13 mm
start of aspiration was 63%. When this time limit was decreased to 1 s after the start of aspiration, the reliability and Blood + EDTA 3 sec.
amount of true-positive results dropped to 33%. 12 mm
When only considering the needles supplied within the packages of the different STF products, the reliability of 13 mm 13 mm
RL + ink 3 sec.
aspiration was 37% (positive within 1 s) and 74% (positive up to 10 s of aspiration), as seen in Table 4. 25 mm 12 mm
ETERMIS 4
13 mm 13 mm
Blood + EDTA 4 sec.
25 mm: 3s 12 mm
Table 3
JUVÉDERM RL + ink 4 sec.
Aspiration test results
VOLBELLA Blood + EDTA 6 sec.
JUVÉDERM RL + ink 4 sec.
PRODUCT AGENT NEEDLE gauge (G), length
VOLIFT Blood + EDTA 5 sec.
23, 19mm 25, 13mm 27, 13mm 28, 19mm 30, 13mm 33, 13mm
JUVÉDERM RL + ink
RL + ink
CONTROL (Saline) VOLUMA Blood + EDTA
Blood + EDTA
JUVÉDERM RL + ink 5 sec. 5 sec. 3 sec.
RL + ink 6 sec. ULTRA 2
BELOTERO Blood + EDTA 9 sec. 8 sec. 4 sec.
HYDRO Blood + EDTA 9 sec.
JUVÉDERM RL + ink 4 sec. 3 sec. 2 sec.
RL + ink 5 sec. ULTRA 3
BELOTERO SOFT Blood + EDTA 4 sec. 4 sec. 3 sec.
Blood + EDTA 4 sec. RL + ink 7 sec. 6 sec.
JUVÉDERM
RL + ink 3 sec. ULTRA 4 Blood + EDTA 10 sec. 10 sec.
BELOTERO
BALANCE JUVÉDERM RL + ink 4 sec. 2 sec. 2 sec. 7 sec.
Blood + EDTA 3 sec. 5 sec. 7 sec.
ULTRA SMILE Blood + EDTA 10 sec. 3 sec. 3 sec.
BELOTERO RL + ink 8 sec. 8 sec. 3 sec.
INTENSE RESTYLANE RL + ink 6 sec 2 sec.
Blood + EDTA 9 sec. 6 sec. 5 sec.
KYSSE Blood + EDTA 3 sec 3 sec.
RL + ink 2 sec.
BELOTERO RESTYLANE RL + ink 9 sec. 10 sec. 7 sec. 2 sec. 8 sec.
VOLUME Blood + EDTA 5 sec. 8 sec. DEFYNE Blood + EDTA
RL + ink RESTYLANE RL + ink 6 sec. 4 sec. 4 sec. 3 sec. 9 sec.
RADIESSE 0.8
(undiluted) REFYNE Blood + EDTA 5 sec. 8 sec.
Blood + EDTA

RL + ink 3 sec. 29G: 4 sec.

RADIESSE 0.8 RL + ink 2 sec. 2 sec.
(diluted) Blood + EDTA RESTYLANE 28G: 8 sec.
LYFT 29G: 4 sec.
RADIESSE 1.5 RL + ink 4 sec. 6 sec. 8 sec. Blood + EDTA
(undiluted) 28G
Blood + EDTA
29G
RL + ink 5 sec. RL + ink 2 sec. 8 sec.
RADIESSE 1.5 28G
RESTYLANE
(diluted)
Blood + EDTA 7 sec. 3 sec. 3 sec. LIDOCAINE 29G
Blood + EDTA
13mm: 4 sec. 28G
RL + ink 4 sec. 3 sec. 20 mm: RL + ink 7 sec. 6 sec. 7 sec. 7 sec.
RESTYLANE
negative VOLYME Blood + EDTA 9 sec. 7 sec. 7 sec.
RADIESSE Plus 1.5
13mm: 6 sec. RL + ink 8 sec. 3 sec. 6 sec.
RESTYLANE
Blood + EDTA 6 sec 3 sec. 20 mm: FYNESSE Blood + EDTA 4 sec. 8 sec.
negative

13 mm 13 mm
RL + ink 5 sec. Positive (within 1 second) Positive (between 1 and 10 seconds) Negative (when still negative after 10 seconds)
20 mm 12 mm
ETERMIS 2 RL: Ringer’s Lactate; EDTA: Ethylenediaminetetraacetic acid
13 mm 13 mm
Blood + EDTA 8 sec.
20 mm 12 mm
Continued on next page

80 chapter 4 81
 results
Table 4
Test results of products with their supplied needles

Merz products Agent Aspiration Merz products Agent Aspiration Allergan products Agent Aspiration Galderma product Agent Aspiration
reliability reliability reliability reliability

Belotero hydro RL + ink Radiesse 0.8 RL + ink Juvéderm volbella RL + ink Restylane kysse (27g) RL + ink
(30 g) (undiluted, 28g) (30g)
Blood + EDTA Blood + EDTA Blood + EDTA Blood + EDTA

Belotero soft RL + ink Radiesse 0.8 RL + ink Juvéderm volift (30g) RL + ink Restylane defyne RL + ink
(30g) (diluted, 28g) (30g)
Blood + EDTA Blood + EDTA Blood + EDTA Blood + EDTA

Belotero balance (27g) RL + ink Radiesse 1.5 RL + ink Juvéderm voluma RL + ink Restylane refyne RL + ink
(undiluted, 28g) (27g) (30g)
Blood + EDTA Blood + EDTA Blood + EDTA Blood + EDTA

Belotero balance RL + ink Radiesse 1.5 RL + ink Juvéderm ultra 2 (30g) RL + ink Restylane lyft RL + ink
(30g) (diluted, 28g) (29g)
Blood + EDTA Blood + EDTA Blood + EDTA Blood + EDTA

Belotero intense (27g) RL + ink Radiesse plus 1.5 (27g, RL + ink Juvéderm ultra 3 (27g) RL + ink Restylane lidocaine RL + ink
20mm) (29g)
Blood + EDTA Blood + EDTA Blood + EDTA Blood + EDTA

Belotero volume (27g) RL + ink Etermis 2 RL + ink Juvéderm ultra 4 (27g) RL + ink Restylane volyme RL + ink
(30g) (27g)
Blood + EDTA Blood + EDTA Blood + EDTA Blood + EDTA

Belotero volume (30g) RL + ink Etermis 2 RL + ink Juvéderm ultra smile RL + ink Restylane fynesse RL + ink
(27g) (27g) (30g)
Blood + EDTA Blood + EDTA Blood + EDTA Blood + EDTA

Etermis 3 RL + ink
(27g) Positive (within 1 second) Positive (between 1 and 10 seconds) Negative (when still negative after 10 seconds)
Blood + EDTA RL: Ringer’s Lactate; EDTA: Ethylenediaminetetraacetic acid

Etermis 4 RL + ink
(27g)
Blood + EDTA

Etermis 4 RL + ink
(25g)
Blood + EDTA

82 chapter 4 83
 discussion
Aspiration before injection is in essence a clinical test, to determine whether the needle tip is inside a blood vessel, be injected. During this repositioning, the needle tip may change position. As one or two millimeters can make the
and therefore, it is a safety test to reduce the risk of intravascular injection. The specificity of an aspiration test is difference between intra- and extravascular injection, the value of the aspiration test is further reduced. Furthermore,
high, as blood in the needle hub indicates a very high probability of intravascular placement (Table 5). However, the when aspirating with a full syringe, a maximum of 0.1 mL negative pressure can be created due to the limitations of
sensitivity of aspiration as a diagnostic test is low (depending on the product and needle tested) as absence of blood the syringe. Our study was performed with a minimum of 0.5 mL negative pressure per product, indicating that in
in the needle hub does not exclude the possibility of intravascular placement of the needle tip, as can be seen from practice false-negative test results could be more likely than in this experimental setup.
the false-negative test results illustrated in Table 3. As a cutoff time of 1 s after aspiration revealed fewer true-positive
results, one could argue that these tests are less reliable compared with those with a cutoff time of 10 s. However, in When considering bevel length, larger gauge needles have greater bevel lengths compared to smaller gauge needles.
clinical practice, physicians usually do not aspirate for more than 1 s. In this case, the orange cells in Table 3 could When an elastic artery is hit and pushed to the periosteum, and then penetrated, the chance of the bevel being in the
also be classified as false-negative test results, making aspiration a highly unreliable test for many STFs when no blood lumen of the artery is greater when a larger gauge needle is used, compared to smaller gauge needles with shorter
is seen in the needle hub during aspiration. bevel lengths. This is especially relevant in anatomic areas where arteries run very close to the periosteum, as seen
in cadaver dissections at the temporal hollows, the periorbital, and the frontal area.18 While this may argue in favor
Our results may also be slightly more conservative than those experienced in routine clinical practice in that we used of using small needles, our study has demonstrated that thinner gauge needles lead to more false-negative test results
a relatively high pressure (150 mm Hg) compared with the world population’s mean systolic blood pressure of 124 and should not be considered safer on the basis of bevel length.
mm Hg as stated by the World Health Organization.14
In the face, the different anatomic regions often have alternative blood supplies, in case an obstruction arises
at one of the arterial sources. It is the authors’ belief that in practice, many patients are injected intra-arterially.
However, because a retrograde injection technique is generally used, the extent of the embolism is limited and an
Table 5 alternative blood supply is sufficient for oxygenation of the affected capillary bed. When the embolus becomes
Aspiration a clinical diagnostic test more voluminous due to static injection inside an artery, a larger capillary bed will be affected, and the chances of
alternative oxygenation are reduced. This is especially true in high-risk areas such as the nose or the glabellar region
The truth where high amounts of end arterioles are present. A recent cadaver study, which sought to determine the amount of
filler necessary to embolize the retina from the supratrochlear artery, found that while the average volume required
Intravascular Extravascular was 0.08 mL, embolization was possible with amounts as small as 0.04 mL.19 In the periorbital area, the maximum
injected volume should therefore not exceed 0.04 mL per bolus when injecting with a needle, considering the
Blood True positive False positive possibility that even though the needle tip might be placed on the periosteum, the lumen might still be intravascular
Test results due to the bevelled needle tip.
No blood False negative True negative
In the current study, the 28-G needle (19 mm) was associated with more false-negative results than the 30-G needle
(13 mm) in a number of tests, for example Belotero Balance. The same was true for the 23-G (19 mm) vs the 25-G
(13 mm) needle tests. When considering the physics of fluid dynamics, pipe resistance (in this case needle lumen)
is determined by diameter and length and possibly surface roughness of the needle lumen. When comparing the
Although blood viscosity is marginally reduced by EDTA, the shape of the viscosity curve is relatively unchanged dimensions of these two needles, the 28-G (or 23-G) needle with its longer length results in a higher flow resistance
when evaluated at different shear rates.15 Blood viscosity is a variable in the reliability of the aspiration test. The during STF aspiration or extrusion than the 30-G (or 25-G) needle, which is in accordance with our results. Test
higher viscosity of blood (3-4 cP) compared with Ringer’s lactate solution (0.7-1 cP) slows down the intraluminar results will therefore be influenced by filler rheology. For example, the rheology of Belotero Balance differs from
movement of liquids, as can be seen in the greater time interval in the blood assay between aspiration and a positive that of Restylane Lidocaine in terms of cohesivity (measured in kPa), and the 28-G (19 mm) needle showed positive
test result. test results with Restylane Lidocaine but negative with Belotero Balance, while the 30-G (13 mm) needle showed
negative test results with Restylane Lidocaine and positive for Belotero Balance. A few papers have examined the
A number of other factors can also influence the effectiveness of aspiration as a safety test. Blood vessels may collapse value of aspiration before injection. In one study which focused on Radiesse, the authors transferred diluted Radiesse
at negative pressure during aspiration, which could prevent blood from entering the syringe. During a preperiosteal to a 1-mL luer lock syringe and used a 27-G needle.20 This syringe has different dimensions and therefore different
injection, there is a chance that the needle may strike an artery and, instead of piercing through, the needle tip may resistance characteristics compared to the syringe supplied by the manufacturer. As seen in our results, both needle
push the elastic artery to the periosteum. During aspiration, one would see no blood, but an embolism could still arise and syringe dimensions may contribute to the reliability of an aspiration test.
after injection, while the bevel of the needle may be intra-arterial even though the needle tip is located on the bone.16
In another recent publication, where the reliability of aspiration as a safety test with different STF materials was also
In a recent study, where the reliability of the aspiration study was examined in a rabbit ear model, results were examined, 60% of the tests were false negative, which is comparable to our results.17
positive for four STF products tested with five different needle sizes.17 However, with in vivo experiments, one can
never be certain that the needle lumen is indeed intra-arterial at the moment of aspiration as hand tremors can For optimal results and accurate product placement, anatomic knowledge is a key. In addition, the risk of intra-arterial
rapidly effect needle tip position. This can lead to a true-negative result under the assumption that the needle is embolisms can be reduced by adhering to the following advice:
placed intravascularly. • Take caution when practicing aspiration as a negative test result (no blood in needle hub) might be false
negative and give the injector a false sense of security;
Technically, aspiration before injection can be challenging. When one aspirates, the plunger needs to be pulled. • When injecting with a sharp point needle, a retrograde technique should be used when the product is
After verifying that there is no blood in the syringe, the fingers are repositioned on the plunger so that the STF can released. In the event that the needle penetrates an artery, only a limited amount of product would then be
released intra arterially;

84 chapter 4 85
 references
• Avoid large-volume bolus injections with the needle in a static position to avoid occlusion of a large area of 1. The American Society for Aesthetic Plastic Surgery. 2016 12. Elert G. “Viscosity”. The physics hypertextbook. (http://
the arterial system; Cosmetic Surgery National Data Bank Statistics. https:// physics.info/ viscosity/). Retrieved December 2015–
• Avoid high-pressure injections as these may lead to retrograde flow against the arterial blood flow into a www.surgery.org/med ia/statistics. Accessed January, 10, February 2016.
proximal arterial system (like the ophthalmic artery); 2017. 13. Haseler L, Sibbitt RR, Sibbitt Jr WL, Michael AA,
• Although nontraumatic cannulas can penetrate arterial walls,21 we recommend using cannulas over 2. Funt D, Pavicic T. Dermal fillers in aesthetics: an overview Gasparovic CM, Bankhurst AD. Syringe and needle size,
needles, and with diameters of 25G and larger to reduce the possibility of penetrating arterial walls; of adverse events and treatment approaches. Clin Cosmet syringe type, vacuum generation, and needle control
• When choosing periosteal bolus injections with a needle, multiple small boluses (0.05 mL per bolus or less) Investig Dermatol. 2013;6:295-316. in aspiration procedures. Cardiovasc Intervent Radiol.
with low pressure should be used. 3. Coleman SR. Avoidance of arterial occlusion from the 2011;34:590-600.
• When injecting in the periorbital area (eg, close to the supratrochlear artery), smaller boluses should be used injection of soft tissue fillers. Aesthet Surg J. 2002;22:555- 14. World Health Organization. Global health observatory
(<0.04 mL) as intravascular injection in this region can cause blindness. 557. data. http:// www.who.int/gho/ncd/risk_factors/blood_
4. Peter S, Mennel S. Retinal branch artery occlusion pressure_prevalence/en/. Accessed April, 19, 2015.
following injection of hyaluronic acid (Restylane). Clin Exp 15. Peker SM, Helvaci SS. Flow of biological fluids in the
Ophthalmol. 2006;34:363- 364. circulatory system. In: Peker SM, Helvaci SS, eds. Solid
5. Sung MS, Kim HG, Woo KI, Kim YD. Ocular ischemia liquid two-phase flow, 1st ed. Amsterdam: Elsevier B.V;
and ischemic oculomotor nerve palsy after vascular 2008:233-234. ISBN: 978-0-444- 52237-5.
embolization of injectable calcium hydroxylapatite filler. 16. Van Loghem JAJ, Humzah D, Kerscher M. Cannula
Ophthal Plast Reconstr Surg. 2010;26:289- 291. versus sharp needle for placement of soft tissue fillers: an
6. Lazzeri D, Agostini T, Figus M, Nardi M, Pantalone M, observational cadaver study. Aesthet Surg J. 2016;sjw220,
Lazzeri S. Blindness following cosmetic injections of the 1-16.
face. Plast Reconstr Surg. 2012;129:994-1012. 17. Casabona G. Blood aspiration test for cosmetic fillers
7. Park SW, Woo SJ, Park KH, Huh JW, Jung C, Kwon OK. to prevent accidental intravascular injection in the face.
Iatrogenic retinal artery occlusion caused by cosmetic Dermatol Surg. 2015;41:841-847.

conclusions 8.
facial filler injections. Am J Ophthalmol. 2012;154:653-
662.
Ozturk CN, Li Y, Tunk R, Parker L, Piliang MP, Zins JE.
18. Pessa JE, Rohrich RJ. The temporal fossa. Facial
topography: clinical anatomy of the face. St Louis, MO:
Quality Medical Publishing, Inc.; 2012:177-218.
Complications following injection of soft-tissue fillers. 19. Khan TT, Colon-Acevedo B, Mettu P, DeLorenzi
Aesthet Surg J. 2013;33:862- 877. C, Woodward JA. An anatomical analysis of the
9. 9. Roberts SA, Arthurs BP. Severe visual loss and orbital supratrochlear artery: considerations in facial filler
Aspiration of STFs as a safety test in this study led to many false-negative results. There are many variables that infarction fol- lowing periorbital aesthetic poly-(L)-lactic injections and preventing vision loss. 2017;37:203-208.
contribute to the sensitivity of aspiration as a clinical test including STF rheology, needle size (lumen, length), acid (PLLA) injection. Oph- thalmic Plast Reconstr Surg. 20. Aguilera SB, Tivoli YA, Seastrom SJ. How to make calcium
needle brand, syringe dimensions, aspiration time, negative pressure created during aspiration, and blood pressure. 2012;28:e68-e70. hydroxylapatite injections safer. J Drugs Dermatol.
Even though a positive test result (blood in the needle hub) can be of great value in clinical practice, we caution 10. Sundaram H, Cassuto D. Biophysical characteristics of 2014;13:1015.
practitioners not to rely on the validity of a negative test result (no blood in the needle hub) due to the high probability hyaluronic acid soft-tissue fillers and their relevance to 21. Yeh LC, Fabi SG, Welsh K. Arterial penetration with blunt-
of a false-negative result. aesthetic applications. Plast Reconstr Surg. 2013;132(4 tipped cannulas using injectables: a false sense of safety?
suppl 2):5S-21S. Dermatol Surg. 2017;43:464-467.
11. Sundaram H, Voigts B, Beer K, Meland M. Comparison of 22. Marmur E, Green L, Busso M. Controlled, randomized
the rheological properties of viscosity and elasticity in two study of pain levels in subjects treated with calcium
Conflict of interest categories of soft tissue fillers: calcium hydroxylapatite hydroxylapatite premixed with lidocaine for correction of
None. and hyaluronic acid. Dermatol Surg. 2010;36:1859-1865. nasolabial folds. Dermatol Surg. 2010;36:309-315.

86 chapter 4 87
 05
Use of Calcium
Hydroxylapatite in the
Upper Third of the Face:
Retrospective Analysis of
Techniques, Dilutions and
Adverse Events.

First author. Impact Factor 1.903, SJR 0.807

Published in Journal of Cosmetic Dermatology. 2018 Oct 25. doi: 10.1111/jocd.12733.

Van Loghem JAJ1

1. Depertment of Ophthalmology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. UMA
Institute private practice, Amsterdam, Netherlands

88 chapter 5 89
 summary
Calcium hydroxylapatite (CaHA) is a commonly used soft area, most with a cannula in the subgaleal space with
tissue filler for aesthetic facial improvement, in particular standard dilution of CaHA (16.7% lidocaine containing
for the lower and mid-face. The golden standard for upper epinephrine). There were 13 treatments to the brow, mostly
facial filler indications is hyaluronic acid (HA) injection. with a cannula and multilevel technique, and 66 treatments
In this report we investigate the safety, efficacy and to the temporal hollows, mostly with a cannula in the
complication rates after injections of CaHA to the upper interfascial space with standard CaHA dilution. No serious
third of the face using a variety of different techniques. This complications were recorded. CaHA was effective and
was a retrospective analysis performed on patients who well-tolerated for a range of upper-face indications. More
had received CaHA in 2016 and 2017 at various dilutions (prospective) research is required to further determine the
in the upper third of the face (frontal area, eyebrows and value of CaHA treatments in these areas.
temporal hollows) using a number of injection techniques
and both blunt-tipped cannulas as well as sharp needles.
Keywords
Records of adverse events and side effects were studied.
brow lift, calcium hydroxylapatite, frontal concavity,
Seventy patients had been injected with CaHA in the upper
soft tissue fillers, temporal hollows
third of the face. There were 36 treatments to the frontal

90 chapter 5 91
 introduction
The use of biostimulatory products in aesthetic medicine has been growing steadily over the past years, and in 2017, Table 1
calcium hydroxylapatite (CaHA, Radiesse®; Merz North America, Inc, Raleigh, NC, USA) had risen to 10th position CaHA vs HA: clinical differences
on the 2017 American Society of Aesthetic Plastic Surgery statistics list for most-sed nonsurgical modalities in the
United States (from 11th position in 2016).1
Soft tissue filler CaHA HA
Calcium hydroxylapatite offers a number of advantages over hyaluronic acid (HA) fillers, as summarized in
Table 1. Due to the high viscoelastic properties of the nondiluted product, it can be used for lifting, volumizing, Volumizing capacity + +
contouring, and treating folds in the face. It is a long-lasting, biodegradable product that stimulates fibroblasts and
neocollagenesis, thereby forming new tissue that consists of the patient’s own collagen and elastin fibers. Contouring capacity + +

In clinical practice, CaHA is not a product for novice injectors as there is currently no reversing agent available, and in Lifting Capacity + +/-
less experienced hands, HA fillers may be a better choice as hyaluronidase can effectively dissolve most HA products
in a matter of hours. There are, however, satisfactory ways for treating CaHA overcorrections and nodules should
Skin rejuvenation capacity ++ +/-
they arise, which generally consist of redistribution methods with massage, injection of saline, and injection of sterile
water.2 A recent report also documents the effective use of a combination of dexamethasone, triamcinolone, and
Risk of granuloma formation - +
5-fluorouracil for the resolution of CaHA nodules.3

Treatability of nodules and overcorrections + ++

Today, 15 years after the introduction of CaHA for aesthetic use, the boundaries of the product are still being explored
with users of CaHA adjusting the rheological and biostimulatory properties by diluting with saline and lidocaine,
opening a whole new spectrum of treatment indications not only in the face, but the rest of the body as well.4–6 Reversal agent available - +

The upper third of the face (forehead, glabella, temples, and crow's feet) is a very important aesthetic area, that Reliability of aspiration as a safety test - -
is, classically treated with botulinum toxin type A as first choice, but often in combination with HA fillers.7 Age
estimation and perceived attractiveness can be positively influenced by treating the face with fillers and toxin.8 Longevity of results + +/-
The periorbital area, including the upper third of the face, plays an important role in interhuman communication
as was established by studying the patterns of saccades and fixations made when viewing a picture of a face for a Patient’s own collagen production is upregulated ++ +/-
few minutes.9
Attracts water (risk of edema) - +

++ very strongly applicable

+ strongly applicable
+/- not convincingly applicable
- not applicable

The optimal treatment approach for using CaHA in the upper face requires careful selection of the appropriate
dilution and instruments for each individual area and target depth. In this study, we aimed to determine which
instrument (sharp needle or blunt-tipped cannula) was preferred at individual anatomical layers and at which CaHA
dilution. As the upper face includes two indications not usually treated with CaHA (crow's feet and glabella), only the
forehead, the temples, and the brows were studied.

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 materials and methods results
This retrospective analysis was performed in a single aesthetic practice over the period 2016-2017. Patients records The records of 70 patients were included in this analysis: nine male, and 61 female with an age range of 30-73 years.
were included if they had received treatment with CaHA in the frontal, temporal and/or brow areas. Files were studied All were ASA-1 (healthy individuals). Details of the instruments used (cannulas or needles), dilutions and adverse
for instruments used (cannula or needle), dilution protocols, injection depth and adverse events. events are shown in Table 2.

For volumization and contouring in the frontal area, subgaleal placement was preferred with the standard dilution
of CaHA with 16.7% lidocaine containing epinephrine (0.3 mL 1% lidocaine with 1:200.000 epinephrine per 1.5
Table 2 mL syringe of CaHA product). Injections were performed using blunt-tipped cannulas and mostly three entry points
Results of retrospective analysis (Figure 1). The temporal crest entry point can be found at the temporal crest, approximately 2 cm cranial to the orbital
rim. Depending on the shape of the frontal concavity, a second temporal crest entry point can be chosen just below
the hairline at the temporal crest. The midline entry point can be found in the midline of the forehead, cranial to the
Area Needle Cannula Unknown Dilutions Depth Adverse Events concavity. From these entry points, a can- nula can be maneuvered through the galea to the subgaleal glide space.
(explanation) While advancing the cannula, no force should be used to pre- vent inadvertent introduction of the cannula into a
blood vessel. When tissue resistance is encountered, the cannula can be rolled between the fingers10,11 and the tissue
Frontal area 1 35 0 ND (0%) Subgaleal space (72.2%) Edema of the upper in front of the cannula lifted with the nondominant hand to create a path of least resistance toward the periosteum
SD (94.4%) Subcutaneous (2.8%) eyelids (SD, n=1), nodu- in front of the cannula tip. For skin rejuvenation in the frontal area the preferred technique used a 1 to 1 dilution
HD (5.6%) Intradermal (2.8%) le (SD, n=1) (50% CaHA plus 50% lidocaine) of CaHA and sharp needle using a serial puncture micro-aliquot technique into the
UK (22.2) dynamic horizontal forehead wrinkles (n = 1) or subcutaneous injection with a blunt-tipped cannula (n = 1). Reduction
of dynamic wrinkles and improvement of brow position was observed after injecting in the subgaleal area of the
Temporal area 4 58 4 ND (10.6%) Submuscular (10.6%) Transient pain on mas- frontal concavity.
SD (78.8%) Interfascial (78.8%) tication (sharp needle,
HD (6.1%) Subcutaneous (1.5%) “gun-shot” technique In the temporal area, interfascial placement was preferred for volumization using the standard dilution of CaHA
UK (4.5%) UK (19.7%) n=2). with 16.7% lidocaine containing epinephrine (0.3 mL 1% lidocaine with 1:200.000 epinephrine per 1.5 mL syringe
Loss of effect of CaHA product). Injections were performed using blunt-tipped cannulas from one or two entry points (Figure 2).
(hyperdilution The temporal crest entry point was the same as that used for the frontal concavity. From there, the cannula can be
interfascial) maneuvered to the periosteum of the frontal bone by pulling the skin and the entry point medially while rolling the
syringe between the fingers so that the cannula can pass the resistance of the galea. Once on the periosteum in the
Brows 1 12 0 ND (15%) Periosteal (0%) Edema>3 days subgaleal space, the direction of the cannula is then changed to lateral. After advancing through the temporal crest,
SD (85%) Multilevel (100%) (ND; n=1) the cannula will be in the interfascial space where multiple retrograde linear threads can be injected. The zygomatic
HD (0%) arch entry point technique, a weak spot can be made in the temporoparietal fascia for the cannula to pass through
(the author suggests to compare the skin thickness after passing through the dermis only overlying the cannula on
lifting up the cannula with the tissue thickness on pulling up the cannula after passing through the temporoparietal
ND = non-diluted. facia; the tissue should look thicker and the cannula should be more limited on pulling up). The cannula will now be
SD = Standard dilution with 0.3 ml adrenalized lidocaine mixed with 1.5 ml CaHA. in the interfascial space and multiple retrograde linear threads may be injected. After volumizing the temporal hollow,
HD = Hyper diluted CaHA (between 0.3 ml and 1.5 ml adrenalized lidocaine per 1.5 ml CaHA). brow position improvement was noticed in some patients. For skin rejuvenation in this area, the preferred technique
UK = unknown (loss of data). used a 50% dilution of CaHA and subcutaneous injection with blunt-tipped cannulas.
Multilevel = both on the periosteum in the deep fat and in the subcutaneous level.
Improving the position of the brows was performed using standard dilution of CaHA with 16.7% lidocaine containing
epinephrine and blunt-tipped cannulas from one entry point using a multilevel technique, both in the periosteal plane
and the subcutaneous layer (Figure 3). The entry point can be found just lateral to the tail of the brow. From there,
the cannula can be advanced in the subcutaneous plane, just below the hairline of the brow and small retrograde
linear threads totaling 0.05-0.1 mL can be injected in order to improve volume and light reflection of the skin
under the brow. The cannula can then be maneuvered to the supraorbital rim, where it can be advanced over the
periosteum until just lateral to the neurovascular bundle of the supraorbital foramen. Small retrograde threads totaling
approximately 0.1-0.2 mL can be injected there. No serious adverse events were recorded. The only adverse events
worth noting are summarized in Table 2. In Figure 4, a before and after example is shown of a patient injected with
CaHA according to the techniques shown in Figures 1–4.

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 results

Figure 1 Figure 2
Schematic drawing of product injection at the frontal concavity. The straight dotted lines mark the temporal Schematic drawing of multilevel cannula technique of the brow lift. The subcutaneous retrograde linear
crest. The black dots at the temporal crest (numbers 1 and 2) and in the midline (number 3) indicate the thread of approximately 0.05 mL is just below the hairline of the tail of the brow. The deep retrograde
entry points. The red lines mark subgaleal retrograde linear threads of CaHA injected from one side (for linear thread of approximately 0.1 mL is on the periosteum of the supraorbital rim, lateral to the
symmetry, the same should be done from the other side). The yellow lines mark optional subgaleal CaHA supraorbital foramen
deposits, depending on the shape of the concavity. Safety note: from the midline entry point, the cannula is
parallel to the direction of the supratrochlear arteries and the area is dense leaving little space for pushing
the arteries to the side. Practitioners are advised to place thumb and index fingers of the nondominant hand
on the supratrochlear notches to prevent retrograde arterial embolism. Furthermore, a maximum injection
volume is advised of 0.04 ml per retrograde linear thread

96 chapter 5 97
 discussion
In aesthetic medicine, the most natural results are achieved by reversing the signs of aging in combination with
reconstruction of a youthful anatomy. One key characteristic of upper facial aging is volume loss. This can be
observed even at a relatively young age and results in a narrowing of the upper face with a loss of the youthful convex
frontal curve, skeletonization of the orbital rim, and a shortened and descending appearance of the eyebrow. To
address these concerns a detailed knowledge of the facial aging process is necessary to develop a proper aesthetic
diagnosis and treatment plan. Soft tissue fillers play an important role in an aesthetic treatment plan by virtue of their
ability to replace lost volume with patients undergoing only a minimally invasive procedure. CaHA has traditionally
been reserved for areas that require large volume replacement or recontouring such as the cheeks and jawline, but it's
use continues to expand to expand to treat a number of indications in the upper face a number of indications in the
upper face.

Calcium hydroxylapatite has several properties that make it an ideal agent for rejuvenation of the upper face including
biodegradable nature, versatility (can mix with lidocaine to change the malleability & rheological properties without
compromising on the efficacy), and its cost-effectiveness. A further benefit of CaHA is that the aesthetic benefits are
not just derived from the volume of product injected, but also from the long-term stimulation of the patient's own
collagen production5,12 leading to a long duration of effect.13 Indeed, we noticed a reduction in dynamic wrinkles in
some patients undergoing subgaleal placement of CaHA. This might be due to a myomodulation effect (stretching
of the muscle reduces basal muscular tonus) and/or to the strengthening of fibrous septae connecting the galea
aponeurotica to the periosteum by neocollagenesis through fibroblast activation. The combined physical properties of
CaHA provides versatility that makes it suitable for most aspects of upper face rejuvenation including line filling, skin
tightening, lifting, contouring and volumizing.

It is important to note that care should be taken when injecting CaHA as there is currently no reversing agent
available. The anatomy of the upper face predisposes it to a higher vascular complication risk, and it is important
to be aware of the danger zones when treating patients. As aspiration is unreliable as a safety test for determining
intravascular placement of the needle, a cannula is preferred for injection of CaHA combined with slow injection of
small amounts of product.14 In the 70 patients included in this study, there were no incidence of vascular compromise
Figure 3 with CaHA. Transient pain on mastication was reported after injection of CaHA in the temple area, as periosteal
Schematic drawing of CaHA injection with blunt cannula in the interfascial space of the temporal hollow. injection with a sharp needle (the so-called “gun-shot” technique) generally results in placement of product in the
The black lines mark the temporal crest, lateral orbital rim, and upper border of the zygomatic arch. The red temporalis muscle due to backflow of the product through the needle trajectory.10
lines indicate retrograde linear threads injection of CaHA from the temporal crest entry point. Yellow lines
indicate possible additional injection of CaHA from the zygomatic arch entry point. Although complications were rare in this case series, they can occur. CaHA nodules (product accumulation) can occur
following injection in dynamic facial areas.15 Late-onset inflammatory reactions have also been observed, but are very
unlikely.16 The most serious adverse events are observed after inadvertent intravascular (intra-arterial) injection and
include tissue necrosis and even blindness.2 Knowledge of the anatomy of the arteries is therefore key to reducing
the risks of complications. In Table 3, a summary of the most important arteries is given in the three treatment areas
described. As arterial anatomy varies widely between individuals, the injector should always be conscious of the fact
that the cannula could be entering a blood vessel. The author therefore recommends the following standard safety
procedures while injecting in the periorbital area:

• Use a cannula whenever possible as cannulas enter blood vessels less easily then sharp needles.
• Inject small amounts of product per bolus or retrograde linear thread.
• Up to 2 cm cranial from the supraorbital rim, the arteries may be found in deep tissue layers; this is a high-risk
zone and extra care should be taken.
• When a cannula is positioned in an area with high tissue tightness (more risk of entering a blood vessel) arteries
are less easily pushed aside. Use delicate handling and inject a maximum of 0.025 mL per retrograde linear thread
or bolus.
• When the direction of the cannula is parallel to the direction of the artery (more risk of entering a blood vessel),
use delicate handling and inject a maximum of 0.025 mL per retrograde linear thread or bolus.

98 chapter 5 99
 references
• When injecting close to arteries, use delicate handling and inject a maximum of 0.025 mL per retrograde linear 1. American Society of Aesthetic Plastic Surgery. Cosmetic 10. 10. Van Loghem, JAJ, Humzah D, Kerscher M Cannula
thread or bolus. Place the thumb and index finger of the nondominant hand on the supratrochlear artery when surgery national databank statistics 2017. https://surgery. versus sharp needle for placement of soft tissue fillers: an
injecting in its vicinity to temporarily block perfusion of this artery and reduce risk of blindness should inadvertent org/sites/default/f iles/ASAPS-Stats2017.pdf. Accessed observational cadaver study. Aesthet Surg J. 2017;38:73-
intra-arterial injection occur. April 13, 2018. 88.
• Use low pressure on injection to prevent retrograde migration of an embolus. 2. Funt D, Pavicic T. Dermal fillers in aesthetics: an overview 11. Van Loghem JA, Yutskovskaya YA, Werschler P. Calcium
of adverse events and treatment approaches. Clin Cosmet hydroxylapatite: over a decade of clinical experience. J
Recently, a hydro-dissection technique has been proposed in which saline is injected into the subgaleal space prior Investig Der- matol. 2013;6:295-316. Clin Aesthet Dermatol. 2015;8(1):38–49.
to injecting CaHA.17 As this technique pushes the arteries away from the treatment target area, it may be regarded 3. Aguilera SB, Aristizabal M, Reed A. Successful treatment 12. 12. Yutskovskaya Y, Kogan E, Leshunov E. A randomized,
as an effective preventative measure to further reduce risk of serious adverse events. In a recent cadaver dissection of calcium hydroxylapatite nodules with intralesional split-face, histomorphologic study comparing a volumetric
study, the authors measured the volume of injectate necessary to reach the ophthalmic artery from the supratrochlear 5-Fluorouracil, dexametha- sone, and triamcinolone. J calcium hydroxylapatite and a hyaluronic acid-based
artery.18 They found that a mean volume of 0.085 mL was sufficient with a spread of 0.04-0.12 mL. As the study only Drugs Dermatol. 2016;15(9):1142-1143. dermal filler. J Drugs Dermatol. 2014;13:1047–1052.
included six cadavers, it can be assumed that lower amounts of volume may be sufficient to cause blindness. It is 4. Casabona G, Pereira G. Microfocused ultrasound with 13. Tsikas TL. A 52-month summary of results using calcium
therefore advised that a maximum injection volume of 0.025 mL per bolus or retrograde linear thread is used when visualization and calcium hydroxylapatite for improving hydroxylapatite for facial soft tissue augmentation.
injecting close to the supratrochlear and supraorbital arteries. This is practical advice as most syringes have 0.05 mL skin laxity and cellulite appearance. Plast Reconstr Surg Dermatol Surg. 2008;34:S9– S15.
markings on their scale so that two retrograde linear threads or boluses can be injected per marking. Glob Open. 2017;5(7):e1388. 14. Van Loghem JA, Fouché JJ, Thuis J. Sensitivity of aspiration
5. Yutskovskaya YA, Kogan EA. Improved neocollagenesis as a safety test before injection of soft tissue fillers. J
The documentation and sharing of injection techniques and treatment results are essential for the development of safe and skin mechanical properties after injection of diluted Cosmet Dermatol. 2018;17(1):39–46.
and effective treatment protocols. Retrospective analysis of patient records from clinical practice reveals that CaHA calcium hydroxylapatite in the neck and décolletage: a 15. Voigts R, DeVore DP, Grazer JM. Dispersion of calcium
is an effective and well-tolerated soft tissue filler for the treatment of age-related volume loss in a number of different pilot study. J Drugs Dermatol. 2017;16(1):68-74. hydroxylapatite accumulations in the skin: animal studies
upper facial areas. 6. Van Loghem JAJ. Use of calcium hydroxylapatite for and clinical practices. Dermatol Surg. 2010;36:798–803.
augmentation of the labia majora and mons pubis. SRL 16. Lemperle G, Gauthier-Hazan N, Wolters M, Eisemann-
Dermatol Clin Res. 2017;2 (1):010-013. Klein M, Zimmermann U, Duffy DM Foreign body
7. Carruthers J, Burgess C, Day D, et al. Consensus granulomas after all injectable dermal fillers: part 1.
recommendations for combined aesthetic interventions in Possible causes. Plast Reconstr Surg. 2009;123:1842–1963.
the face using botulinum toxin, fillers, and energy-based 17. Chao YYY. Saline hydrodissection: a novel technique
devices. Dermatol Surg. 2016;42:586-597. for the injection of calcium hydroxylapatite fillers in the
8. Scerbakova P, Scerbakov A, Gründl M, van Loghem J, forehead. Dermatol Surg. 2018;44(1):133–136.
Kerscher M. Minimally invasive combination treatment 18. Khan TT, Colon-Acevedo B, Mettu P, DeLorenzi
with toxin and filler and its impact on perceived C, Woodward JA. An anatomical analysis of the
attractiveness and age. EADV.2016, eposter. supratrochlear artery: considerations in facial filler
9. Yarbus A. Eye Movements and Vision. New York, NY: injections and preventing vision loss. Aesthet Surg J.
Plenium Press; 1967. 2017;37(2):203–208.

Figure 4
Left: baseline, right: 3 mo after injection of 3 mL CaHA (standard dilution). Frontal concavity (subgaleal
space): 1.2 mL with a 3-point cannula technique as in Figure 1. Brows (multilevel technique): 0.3 mL cannula
technique as in Figure 2. Temporal hollows (interfascial space): 1.5 mL with a 1-point cannula technique as in
Figure 3. Note the reduction of horizontal forehead lines and improved brow position

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 06
Left/Right Pain Asymmetry
With Injectable Cosmetic
Treatments for the Face.

Second author. Impact Factor 2.824, SJR 1.434

Published in Aesthetic Surgery Journal. 2017 Jun 1;37(6):708-714. doi: 10.1093/asj/sjw214

Fouché JJ1, Van Loghem JAJ1,2, Thuis J1, De Heer LM3, van Oijen MGH4.

1. Depertment of Ophthalmology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
2. UMA Institute private practice, Amsterdam, Netherlands
3. Department of Cardiothoracic Surgery, University Medical Centre Utrecht, Netherlands
4. Department of Medical Oncology, Academic Medical Centre, University of Amsterdam, Netherlands

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 abstract
Background Results
Pain is processed and experienced differently on the Combined mean VAS scores for BTX and STF treatments
left (L) and right (R) sides of the body; however, L/R pain (L, 3.79 vs R, 3.42), and individual scores for BTX (L, 3.60
asymmetry with cosmetic treatments of the face has not vs R, 3.30) or STF (L, 4.22 vs R, 3.69) treatments were
been evaluated. significantly different, with pain rated as worse on the L side
of the face (all P < 0.01). When treatments were performed
Objectives first on the L side, patients rated the overall experience as
The authors compared patient ratings of L/R facial significantly less painful than when treatments were begun
pain during and immediately after injectable on the R side. BTX treatments with a 29-gauge (G) needle
cosmetic treatments. were significantly more painful than with a 33-G needle.

Methods Conclusions
In this cross-sectional multicenter pragmatic study, pain To lessen pain with injectable facial treatments, the authors
levels were evaluated for 302 patients who underwent recommend placing the first injection on the L side of the
facial treatments with botulinum toxin (BTX) and/or face and, when possible, employing a high-G needle.
impermanent soft-tissue filler (STF). Patients indicated pain
intensity on each side of the face with a visual analogue Level of Evidence: 2
scale (VAS; 0, no pain; 10, worst pain).

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 introduction methods
Injectable cosmetic treatments have become popular in recent years. Botulinum toxin (BTX) and soft-tissue filler (STF) Patients who underwent aesthetic facial treatments with BTX and/or STF (ie, calcium hydroxyapatite and/or hyaluronic
were the 2 most frequently administered nonsurgical facial treatments in the United States in 2015 (4.3 million and acid) at 5 aesthetic medicine training institutes in the Netherlands, from May 2015 to August 2015, were evaluated
2.1 million procedures, respectively).1 Since 1997, the number of BTX procedures in the United States has increased in a cross-sectional multicenter pragmatic study. The study was not blinded, and a control group was not included.
by 6448.9%.1 With BTX and STF treatments, patients experience minimal downtime compared with surgical All patients were ≥18 years of age. Exclusion criteria were neurological disorders or objective differences on the
aesthetic procedures. Nevertheless, BTX and STF injections are associated with adverse events that may be mild R and L sides of the face regarding response to touch, pain, pressure, or temperature. This study was approved by
(eg, bruising, edema, skin discoloration), moderate (eg, infection, nodular masses, paresthesia), or rarely, severe (eg, the Medical Ethical Committee of the Academic Medical Center of the University of Amsterdam (Netherlands) and
vascular compromise).2 was conducted in accordance with guidelines set forth in the Declaration of Helsinki. At the first pretreatment visit,
the study was described to patients by reception staff, and patients provided informed consent and completed an
Minimizing pain and discomfort during a nonsurgical procedure is essential to patient satisfaction. In our experience, initial questionnaire (Appendix A, available as Supplementary Material at www.aestheticsurgeryjournal.com). Tactile
patients who undergo facial rejuvenation with BTX and/or STF often remark that treatment was more painful on 1 side asymmetry of the face was determined objectively by applying a cotton swab while the patient’s eyes were closed.
than on the other. Discussing this phenomenon with the patient often involves speculative explanations and theories Patients also were asked whether they regarded themselves as having asymmetric facial sensitivity.
that are not evidence-based. However, investigators have determined that patients perceive exposure of their hands to
pressure or extreme temperatures as being significantly more painful in the left (L) hand than the right (R).3-5 Results of The side of the face to receive the first injection was predetermined randomly. Specifically, medical forms were
neuroimaging studies indicate that pain processing is predominantly localized in the R hemisphere in specific regions numbered consecutively as patients agreed to participate in the study. Patients whose form had an uneven number
of the cortex, and the existence of an R-lateralized attentional system to alert organisms to pain has been proposed.6-9 received the first injection on the L side of the face, and those with even-numbered forms received the first injection
Moreover, processing of negative emotions, symptoms of depression, and pain correlates significantly with increased on the R side. Each patient received BTX and/or STF treatment from 1 physician. Physicians with experience
activity of the R frontal lobe.10-14 Various closely linked biological and psychological mechanisms affect the experience performing injectable cosmetic treatments for the face were present at all 5 participating institutes. (Clinic 28 included
of pain. The relationships among these mechanisms have been described by Melzack and Wall.15 In 1965, these 1 physician with 4 years of experience; Clinique Dr Don included 2 physicians with 1 and 16 years of experience;
authors proposed the gate control theory of pain, which states that a non-noxious stimulus can suppress pain.15 Other DermaClinic included 3 physicians with 1, 2, and 13 years of experience; Doctors Inc / UMA Institute. included 3
investigators have applied and extended the gate control theory to understand the power of mental distraction and to physicians with 1, 2, and 12 years of experience; and Kliniek aan de Maas included 2 physicians with 2 and 23 years
utilize competing stimuli to lessen pain perception (ie, conditioned pain modulation).16 of experience.)

Herein, we describe our findings of pain intensity perceptions on the L and R sides of the face for patients who Within 5 minutes after treatment, patients were asked to rate the degree of pain on each side of the face on a visual
underwent BTX and/or STF treatment. analogue scale (VAS) ranging from 0 (no pain) to 10 (worst pain) at 0.5-unit intervals. Responses were recorded on
a form that lacked identifying information other than the study number (Appendix B, available as Supplementary
Material at www.aestheticsurgeryjournal.com). VAS scores were analyzed with Microsoft Excel for Mac 2011 software
(version 14.6.2; Redmond, WA). Distributions were determined for baseline characteristics, and data for the 2 sides of
the face were compared with paired 2-tailed t tests. Subgroup analyses were performed to evaluate patient-specific
information (eg, handedness, gender), treatment characteristics (eg, needle size), and overall pain perceptions for BTX
vs STF. Statistical significance was defined as P < 0.05.

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 results
A total of 315 patients agreed to participate in the study. Some data were incomplete for 19 patients; 13 of these All physicians who administered study treatments were R-handed, and there were no significant differences in the
patients were excluded from the study because the treatment or study protocol was not followed correctly (n = 4) or number of treatments performed by each physician. BTX treatments were delivered with needles, whereas STF
because key data (eg, VAS scores) were missing (n = 9). The remaining 302 patients (283 [94%] women) were included treatments were delivered with needles or cannulae. The specific materials (dermal products and needle/cannula
in the analyses. In total, 349 treatments were performed (244 BTX, 105 STF). The patients’ mean age was 43 years sizes) utilized at each institute are listed in Table 2. With the exception of minor bruising, no other adverse effects
(standard deviation [SD], 11 years; range, 21–76 years), and 33 patients (11%) were L-handed. Baseline characteristics were observed during or after the treatments.
of patients and treatments performed are summarized in Table 1.

Table 2
Table 1 Materials Applied for Injectable Cosmetic Treatments at Each Clinic
Baseline Characteristics of Patients Overall and per Institute

Clinic 28 Clinique Dr Don Derma Clinic Doctors Inc Kliniek aan de

Patient Information Total Subgrouped by Institute Maas

BTX
Azzalure •
Clinic 28 Clinique DermaClinic Doctors Kliniek aan
Dr Don Inc de Maas Botox •
Xeomin • • •
No. of patients (%) 302 (100) 47 (15.6) 44 (14.6) 54 (17.9) 138 (45.7) 19 (6.3) Buffereda • •
STF
Mean age, y (range) 43.10 (21-76) 44.00 (21-69) 42.63 (21-62) 50.98 (27-75) 39.50 (22-76) 46.37 (21-66)
Hyaluronic acid
Belotero Balance • • •
No. of men (%) 19 (6.3) 4 (1.3) 6 (2.0) 0 (0.0) 9 (3.0) 0 (0.0) Belotero Hydro •
Belotero Intense • • •

No. of women (%) 283 (93.7) 43 (14.2) 38 (12.6) 54 (17.9) 129 (42.7) 19 (6.3) Belotero Soft • • •
Belotero Volume • • •
Emervel •
No. of excluded patients (%) 13 (4.3) 0 (0.0) 6 (2.0) 3 (0.9) 4 (1.3) 0 (0.0)
Juvéderm Ultra 2 •
Juvéderm Ultra 3 •
L 33 (10.9) 7 (2.3) 4 (1.3) 6 (2.0) 12 (4.0) 4 (1.3)
Juvéderm Ultra 4 •
Handedness (%) Juvéderm Volbella • • •
R 269 (89.1) 40 (13.2) 40 (13.2) 48 (15.9) 126 (41.7) 15 (5.0)
Juvéderm Volift • •
Juvéderm Voluma • •

L 20 (6.6) 7 (2.3) 4 (1.3) 2 (0.7) 7 (2.3) 0 (0.0) Restylane •

Side of increased Calcium hydroxyapatite
facial sensitivity (%)a
Radiesse • • • • •
R 5 (1.7) 1 (0.3) 1 (0.3) 2 (0.7) 1 (0.3) 0 (0.0)
Cannula size, G

No. of patients 19 (6.3) 0 (0.0) 6 (2.0) 4 (1.3) 9 (3.0) 0 (0.0) 25 • • • •

with incomplete data (%) 27 • • • •
Needle size, G
BTX 244 39 40 38 109 18
25 •
No. of interventions
STF 105 19 10 21 50 5 27 • • • • •
29 •
BTX, botulinum toxin; L, left; R, right; STF, soft-tissue filler. aAsymmetric facial sensitivity was based on the 30 • • • •
patient’s own subjective assessment.
33 • • • •

108 chapter 6 109

 Table 2: BTX, botulinum toxin; G, gauge; STF, soft-tissue filler. Manufacturer information for BTX is as Table 3
follows: abobotulinumtoxin A (Azzalure, Galderma Pharma SA, Lausanne, Switzerland), onabotulinumtoxin VAS Scores for BTX and/or STF Treatments
A (Botox, Allergan Inc, Irvine, CA), and incobotulinumtoxin A (Xeomin, Merz Pharmaceuticals GmbH,
Frankfurt, Germany). Manufacturer information for STF is as follows: calcium hydroxylapatite (Radiesse,
Merz Pharmaceuticals GmbH), hyaluronate (18 mg/mL, glycerol 21 mg/mL; Belotero Hydro, Merz Subgrouped by Institute

Pharmaceuticals GmbH), hyaluronic acid (17.5 mg/mL; Juvéderm Volift, Allergan Inc), hyaluronic acid (20
Clinic 28 Clinique Dr Don DermaClinic Doctors Inc Kliniek aan de Maas
mg/mL; Belotero Soft, Merz Pharmaceuticals GmbH), hyaluronic acid (20 mg/mL; Juvéderm Voluma,
Side of Face Mean SD P Side of Face Mean SD Side of Face Mean SD Side of Face Mean SD Side of Face Mean SD Side of Face Mean SD
Allergan Inc), hyaluronic acid (20 mg/mL; Restylane, Galderma Pharma SA), hyaluronic acid (20 mg/mL; VAS VAS VAS VAS VAS VAS

Emervel, Galderma Pharma SA), hyaluronic acid (22.5 mg/mL; Belotero Balance, Merz Pharmaceuticals
No. of patients (%) 302 (100) 47 (15.6) 44 (14.6) 54 (17.9) 138 (45.7) 19 (6.3)
GmbH), hyaluronic acid (24 mg/mL; Juvéderm ULTRA 2, Allergan Inc), hyaluronic acid (24 mg/mL;
L 3.60 1.86 L 3.31 1.73 L 2.83 1.55 L 4.83 1.93 L 3.70 1.81 L 2.72 1.53
Juvéderm ULTRA 3, Allergan Inc), hyaluronic acid (24 mg/mL; Juvéderm ULTRA 4, Allergan Inc), hyaluronic
< .01

acid (24 mg/mL; Juvéderm Volbella, Allergan Inc), hyaluronic acid (25.5 mg/mL; Belotero Intense, Merz No. of BTX treatments 244 R 3.30 1.93 39 R 2.79 1.63 40 R 2.73 1.65 38 R 4.41 2.29 109 R 3.52 1.81 18 R 2.00 1.64

Pharmaceuticals GmbH), and hyaluronic acid (26 mg/mL; Belotero Volume, Merz Pharmaceuticals GmbH).
Sum 6.90 Sum 6.10 Sum 5.55 Sum 9.24 Sum 7.22 Sum 4.72

aSaline for reconstitution of BTX was buffered to physiological pH with sodium hydrogen carbonate.
L 4.22 1.97 L 3.58 1.74 L 4.00 1.94 L 4.21 1.65 L 4.62 2.14 L 3.20 1.92

< .01

No. of STF treatments 105 R 3.69 1.92 19 R 2.84 1.46 10 R 4.00 2.05 21 R 3.60 2.06 50 R 4.11 1.93 5 R 2.40 1.52

Sum 7.91 Sum 6.42 Sum 8.00 Sum 7.81 Sum 8.73 Sum 5.60
Results of pain severity by treatment modality are depicted in Figure 1 and Table 3. For BTX and STF treatments,
patients reported significantly higher VAS scores (ie, more painful) for the L side of the face. When VAS scores for BTX L 3.79 1.91 L 3.40 1.73 L 3.06 1.68 L 4.61 1.85 L 3.99 1.96 L 2.83 1.59

< .01
and STF treatments were combined, these ratings remained significantly higher for the L side of the face. Moreover, Total No. of BTX + STF
349 R 3.42 1.93 58 R 2.81 1.56 50 R 2.98 1.79 59 R 4.12 2.23 159 R 3.70 1.86 23 R 2.09 1.59
treatments
STF treatments were perceived as more painful than BTX treatments. VAS scores according to patient handedness
and the side of initial injection are shown in Supplemental Table 1 (available as Supplementary Material at www. Sum 7.20 Sum 6.21 Sum 6.04 Sum 8.73 Sum 7.69 Sum 4.91

aestheticsurgeryjournal.com). R-handed patients (n = 269) reported significantly higher individual and combined VAS
scores for BTX and/or STF treatments than did L-handed patients (n = 33). Patients who underwent the first injection BTX, botulinum toxin; G, gauge; STF, soft-tissue filler. Manufacturer information for BTX is as follows:
on the L side of the face (n = 151) reported significantly lower individual and combined VAS scores for BTX and/or abobotulinumtoxin A (Azzalure, Galderma Pharma SA, Lausanne, Switzerland), onabotulinumtoxin
STF treatments than did patients who received the first treatment on the R side (n = 198). The reported individual and A (Botox, Allergan Inc, Irvine, CA), and incobotulinumtoxin A (Xeomin, Merz Pharmaceuticals GmbH,
combined VAS scores for BTX and/or STF treatments were lower for men (n = 19) than women (n = 283) (Table 4). Frankfurt, Germany). Manufacturer information for STF is as follows: calcium hydroxylapatite (Radiesse,
Compared with the 4 other participating institutes, DermaClinic tended to have higher combined VAS scores for BTX Merz Pharmaceuticals GmbH), hyaluronate (18 mg/mL, glycerol 21 mg/mL; Belotero Hydro, Merz
and STF treatments and had substantially higher VAS scores for BTX alone (Table 3). At DermaClinic, BTX treatments Pharmaceuticals GmbH), hyaluronic acid (17.5 mg/mL; Juvéderm Volift, Allergan Inc), hyaluronic acid (20
were administered with a 29-gauge (G) needle, whereas a 33-G needle was employed at the other institutes (Table 2). mg/mL; Belotero Soft, Merz Pharmaceuticals GmbH), hyaluronic acid (20 mg/mL; Juvéderm Voluma,
Allergan Inc), hyaluronic acid (20 mg/mL; Restylane, Galderma Pharma SA), hyaluronic acid (20 mg/mL;
Emervel, Galderma Pharma SA), hyaluronic acid (22.5 mg/mL; Belotero Balance, Merz Pharmaceuticals
GmbH), hyaluronic acid (24 mg/mL; Juvéderm ULTRA 2, Allergan Inc), hyaluronic acid (24 mg/mL;
5.0 0 Juvéderm ULTRA 3, Allergan Inc), hyaluronic acid (24 mg/mL; Juvéderm ULTRA 4, Allergan Inc), hyaluronic
4.22 acid (24 mg/mL; Juvéderm Volbella, Allergan Inc), hyaluronic acid (25.5 mg/mL; Belotero Intense, Merz
4.0 0 3 .6 9 3 .7 9 Pharmaceuticals GmbH), and hyaluronic acid (26 mg/mL; Belotero Volume, Merz Pharmaceuticals GmbH).
3 .6 0
3.30 3 .4 2
aSaline for reconstitution of BTX was buffered to physiological pH with sodium hydrogen carbonate.
Mean VAS

3.0 0

2.0 0

1.0 0

0.0 0
L R L R L R

BTX STF BTX + STF

Figure 1
Pain intensity ratings on a visual analog scale (VAS; 0, no pain; 10, worst pain). Bars indicate mean values;
error bars indicate standard error of the mean. L, left side of the face; R, right side of the face; BTX, botulinum
toxin treatment; STF, soft-tissue filler treatment.

110 chapter 6 111

 discussion
Table 4 We demonstrated that, during and shortly after bilateral facial treatment with BTX and/or STF, patients experienced
Baseline Characteristics of Patients and VAS Scores by Gender significantly more pain on the L side. However, when the first BTX and/or STF injection was made on the L side of the
face, patients rated the overall treatment as less painful than when the first injection was made on R side of the face.
Men Women Moreover, STF treatments were perceived as more painful than BTX treatments, and R-handed patients experienced
more pain than L-handed patients with BTX and STF treatments. For BTX treatments, a smaller needle diameter was
No. of patients (%) 19 (6.3) 283 (93.7)
associated with less pain (Tables 2 and 3).
Mean age, y (range) 44.53 (27-69) 43.00 (21-76)

Patient handedness (%) L 2 (0.7) 31 (10.3) To our knowledge, this is the first study to address R/L facial pain severity with BTX and/or STF treatment. The VAS
is a standard, highly efficient method to assess pain intensity. To evaluate pain level more specifically, our VAS
R 17 (5.6) 252 (89.0)
contained intervals of 0.5 rather than 1.0 (as in the typical scale). Our observations support that specific adjustments
Side of increased facial L 1 (0.3) 19 (83.4) to injection techniques may decrease pain and discomfort, and in turn, yield greater patient satisfaction.
sensitivity (%)a Various studies have addressed pain asymmetry after the application of noxious stimuli to the hands and/or arms. In a
R 1 (0.3) 4 (1.3)
study by Sarlani et al,3 40 healthy individuals rated pain intensity when the L or R hand was immersed in hot or cold
No. of patients with incomplete data (%) 0 (0.0) 19 (6.3) water (temperature range, 10°C and 47°C).
Intervention No. Side of Mean SD P No. Side of Mean SD P
face VAS face VAS They found that individuals perceived greater pain when the L hand was immersed.3 Pauli et al4 examined pain
BTX 15 L 3.10 1.81 .55 229 L 3.63 1.86 .02 thresholds for 8 participants by means of electroencephalography for a 6-week period; pain thresholds were lower
for the L hand. In a study by Lugo et al,5 351 participants immersed both hands in a 48°C water bath for 15 seconds
R 3.40 2.05 R 3.28 1.93
and reported pain severity on a VAS. Pain was significantly worse for the L hand.5 Spernal et al10 evaluated thresholds
Sum 6.50 Sum 6.91 for pressure, cold, and heat pain on the R/L forearm or hand for healthy patients (n = 20) and for patients with
major depressive disorder (n = 21) or panic disorder (n = 21). These authors found that participants had greater pain
STF 4 L 2.50 1.29 .22 101 L 4.29 1.96 < .01 sensitivity on the L side for pressure, but no pain asymmetry for cold/heat stimuli.10 Findings of these studies are
consistent with those of our study of facial pain asymmetry and support the phenomenon that patients perceive pain
R 3.25 1.71 R 3.70 1.94
as being more intense on the L side of the body.
Sum 5.75 Sum 8.03
Pauli et al17 compared pressure pain threshold (PPT) asymmetry for 12 R-handed and 12 L-handed patients and found
Combined BTX + STF 19 L 2.97 1.70 .33 330 L 3.83 1.91 < .01 that R-handed patients experience PPT asymmetry, with greater pain sensitivity in the L hand. This association with
handedness is similar to our results, in which R-handed patients scored BTX and STF treatments as more painful
R 3.37 1.94 R 3.41 1.94 than did L-handed patients. Several investigators also have demonstrated that women have lower thresholds of pain
sensitivity and enhanced pain facilitation compared with men.18,19 This finding has been attributed to a complex array
Sum 6.34 Sum 7.24
of factors, ranging from biologic (eg, hormonal, genetic) to psychologic (eg, pain coping) to sociocultural (eg, gender
roles).18,19 Similarly, we demonstrated that BTX and STF treatments were perceived as more painful by women.
BTX, botulinum toxin; L, left; R, right; SD, standard deviation; STF, soft-tissue filler; VAS, visual analogue
scale. a. Asymmetric facial sensitivity was based on the patient’s own subjective assessment. Arendt-Nielson et al20 evaluated the effects of needle outer diameter (23 G, 27 G, 30 G, and 32 G) on pain frequency,
pain intensity, and occurrence of bleeding. Consistent with our study, these authors concluded that needle size
correlates positively and significantly with the frequency of pain during insertion.20 The 5 clinics in our study had
different needle/cannula preferences for STF treatments, and therefore we could not conclude whether patients
experienced more pain with needles or cannulae. The safety of needles for STF treatments currently is under debate
and warrants additional research, especially for regions of the face in which intravascular placement of needles could
lead to severe complications.

Our study had several limitations. All physicians who performed treatments in this study were R-handed. It is possible
that the approach and orientation of the physician on either side of the patient’s face could differ by physician
handedness. Physicians positioned themselves on the side of the patient that was undergoing treatment, rather than
leaning over the patient to perform the contralateral treatment. We believe that this method ensured optimal delivery
distances and physical ergonomics for both sides of the face.

Although we intended, through randomization, to have an equal number of patients receive their first injection on
each side, ultimately we determined that 131 patients (43%) initially were treated on the L side and 171 patients
(57%) on the R side (Supplemental Table 1). (Forty-two patients were incorrectly treated first on the R side, and 2
patients were incorrectly treated first on the L side.) Physician handedness likely contributed to this. Several physicians

112 chapter 6 113

 references
disregarded or forgot the assigned starting treatment side. In our experience, most physicians (especially R-handed 1. Cosmetic surgery national data bank statistics. Aesthet 11. Canli T, Desmond JE, Zhao Z, Glover G, Gabrieli JD.
physicians) naturally approach patients from the R side for examination and treatment. When these 44 patients Surg J. 2016;36(Suppl 1):1-29. Hemispheric asymmetry for emotional stimuli detected
(51 treatments) were removed from the analyses, our results were unchanged. Therefore, we do not believe that 2. Funt D, Pavicic T. Dermal fillers in aesthetics: an overview with fMRI. Neuroreport. 1998;9(14):3233-3239.
incomplete randomization compromised this study. of adverse events and treatment approaches. Clin Cosmet 12. Otto MW, Dougher MJ, Yeo RA. Depression, pain, and
Investig Dermatol. 2013;6:295-316. hemispheric activation. J Nerv Ment Dis. 1989;177(4):210-
Our pragmatic study design obviated any neurophysiologic explanation for our findings. In addition, matching was 3. Sarlani E, Farooq N, Greenspan JD. Gender and laterality 218.
omitted, and we did not perform sample-size calculations in advance of this study. Therefore, the statistical power differences in thermosensation throughout the perceptible 13. Hecht D. Depression and the hyperactive right-
for subgroup analyses of patient handedness and gender was limited. Sample sizes for all other comparisons were range. Pain. 2003;106(1-2):9-18. hemisphere. Neurosci Res. 2010;68(2):77-87.
more than adequate. Because we did not include any control groups, blinding was not needed. We cannot rule out 4. Pauli P, Wiedemann G, Nickola M. Pain sensitivity, 14. Wasan AD, Anderson NK, Giddon DB. Differences in
that the lack of blinding may have biased physicians’ techniques (eg, carrying out treatments differently or delivering cerebral laterality, and negative affect. Pain. 1999;80(1- pain, psychological symptoms, and gender distribution
more treatments to 1 side of the face). However, baseline characteristics of the treatment groups did not differ 2):359- 364. among patients with left- vs right-sided chronic spinal
significantly with respect to age, race, or asymmetry of facial sensitivity. We are confident that physicians in this study 5. LugoM,IstúrizG,LaraC,GarcíaN,Eblen-ZaijurA.Sensory pain. Pain Med. 2010;11(9):1373-1380.
sought to minimize patient discomfort and achieve good aesthetic results and would not intentionally introduce pain lateralization in pain subjective perception for noxious 15. Melzack R, Wall PD. Pain mechanisms: a new theory.
asymmetry. Although we did not collect data regarding the number of injections per patient on each side of the face, heat stimulus. Somatosens Mot Res. 2002;19(3):207-212. Science. 1965;150(3699):971-979.
patients who undergo BTX and/or STF treatments typically receive an equal number of injections on the R and L sides. 6. Symonds LL, Gordon NS, Bixby JC, Mande MM. Right- 16. Yarnitsky D. Conditioned pain modulation (the diffuse
Topical anesthetics or ice packs were applied for a few patients, and some patients received injections of local lateralized pain processing in the human cortex: an FMRI noxious inhibitory control-like effect): its relevance for
anesthetic (especially for STF treatment) before the site was prepared for cannula insertion. Although patients who study. J Neurophysiol. 2006;95(6):3823-3830. acute and chronic pain states. Curr Opin Anaesthesiol.
received pain management would likely have experienced less pain, anesthetics were applied to both sides of the 7. 7. Brooks JC, Nurmikko TJ, Bimson WE, Singh KD, 2010;23(5):611-615.
face, so we maintain that L/R discrepancies in pain intensity would be preserved. Roberts N. fMRI of thermal pain: effects of stimulus 17. Pauli P, Wiedemann G, Nickola M. Pressure pain
laterality and attention. Neuroimage. 2002;15(2):293-301. thresholds asymmetry in left- and right-handers:
STF formulations vary in rheologic properties (eg, cohesiveness, viscosity, elasticity) and, therefore, the pain intensities 8. Coghill RC, Gilron I, Iadarola MJ. Hemispheric Associations with behavioural measures of cerebral
elicited also may differ. However, the pain experienced during and immediately after STF treatment largely is caused lateralization of somatosensory processing. J laterality. Eur J Pain. 1999;3(2):151-156.
by needle insertion and the expansion of tissue upon delivery of the filler. After some time, an STF with a low G prime Neurophysiol. 2001;85(6):2602-2612. 18. Bartley EJ, Fillingim RB. Sex differences in pain: a brief
could integrate and disperse more easily into surrounding tissue, potentially decreasing pressure on tissue, and in turn, 9. Youell PD, Wise RG, Bentley DE, et al. Lateralisation of review of clinical and experimental findings. Br J Anaesth.
decreasing pain. nociceptive processing in the human brain: a functional 2013;111(1):52-58.
magnetic resonance imaging study. Neuroimage. 19. Melchior M, Poisbeau P, Gaumond I, Marchand S. Insights
2004;23(3):1068-1077. into the mechanisms and the emergence of sex-differences
10. Spernal J, Krieg JC, Lautenbacher S. Pain thresholds in pain. Neuroscience. 2016;338:63-80.
as a putative functional test for cerebral laterality 20. Arendt-Nielsen L, Egekvist H, Bjerring P. Pain following
in major depressive disorder and panic disorder. controlled cutaneous insertion of needles with different

conclusions Neuropsychobiology. 2003;48(3):146-151. diameters. Somatosens Mot Res. 2006;23(1-2):37-43

To lessen the pain and discomfort associated with administration of BTX and/or STF, patients should first be treated on
the L side of the face, and when possible, a high-G needle should be employed.

Supplementary Material
This article contains supplementary material located online at www.aestheticsurgeryjournal.com.

Disclosures
The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of
this article.

Funding
The authors received no financial support for the research, authorship, and publication of this article.

114 chapter 6 115

 supplementary data
Appendix A. Supplemental Table 1.
Baseline Questionnaire Baseline Characteristics, Patient Handedness, and Facial Side Treated First
Appendix A. Baseline Questionnaire
TREATMENT DATA (TO BE FILLED IN BY TREATING PHYSICIAN) SUBJECT NUMBER: Patient Handedness Side of Face Treated First
SIDE TREATED FIRST: L / R Total(s)
TACTILE DISCREPANCY? NO / R: Baseline
L R L R
L: Characteristics
Date: / / 2015
Institute: Doctors Inc. / Clinic 28 / Kliniek aan de Maas / DermaClinic / Clinique Dr Don No. of patients (%) 33 (10.9) 269 (89.1) 131 (43.4) 171 (56.6) 302
Treatment modalities: Botulinum toxin / Soft tissue filler
Date of birth: / / 19 43.33 43.07 41.91 44.01
Mean age (range), y 22-61 21-76 21 - 68 21-76
43.10

QUESTIONNAIRE (BLACK HIGHLIGHTED TEXT TO BE FILLED IN BY PATIENT)

No. of men (%) 2 (0.7) 17 (5.6) 4 (1.3) 15 (5.0) 19
BEFORE TREATMENT No. of women (%) 31 (10.3) 252 (83.4) 127 (42.1) 156 (51.7) 283
Handedness L 10 (3.3) 23 (7.6) 33
1) Any previous treatment to the face in the form of surgery (major or minor invasive), laser, light, or chemical NA NA
(%) R 121 (40.1) 148 (49.0) 269
substances/peelings?
Side of L 3 (1.0) 17 (5.6) 12 (4.0) 8 (2.6) 20
increased facial
YES NO sensitivity (%)a R
0 (0.0) 5 (1.7) 3 (1.0) 2 (0.7) 5
If YES, please clarify + when: No. of patients with
incomplete data (%) 0 (0.0) 19 (6.3) 4 (1.3) 5 (1.7) 19; 9
2) Any neurological diseases in the past or present?
Side Side Side Side
Mean Mean Mean Mean
YES NO Intervention No. of
VAS
SD P No. of
VAS
SD P No. of
VAS
SD P No. of
VAS
SD P NA
face face face face
If YES, please clarify + when:

3) Left- or right-handed (when writing)? L 3.04 1.82 L 3.65 1.86 L 3.44 1.82 L 3.72 1.89
.07 .01 .50 < .01
BTX 23 R 2.54 1.85 221 R 3.38 1.93 106 R 3.36 1.85 138 R 3.25 2.00 244
LEFT RIGHT
Sum 5.59 Sum 7.03 Sum 6.80 Sum 6.97
4) Any difference in feeling in the face (right vs. left) on own account?
L 4.06 1.48 L 4.26 2.06 L 4.34 2.22 L 4.15 1.79
YES NO .02 .01 < .01 .05
If YES, please clarify: STF 17 R 3.24 1.60 88 R 3.77 1.97 45 R 3.54 1.83 60 R 3.79 2.00 105

Sum 7.29 Sum 8.03 Sum 7.88 Sum 7.94

5) Throughout our lives, most of us have had pain from time to time (such as minor headaches, sprains, tooth
aches). Have you had pain other than these everyday kinds of pain during the LAST WEEK?
L 3.48 1.74 L 3.83 1.93 L 3.71 1.98 L 3.84 1.86
< .01 < .01 .02 < .01
YES NO Combined
40 R 2.84 1.76 309 R 3.49 1.95 151 R 3.41 1.84 198 R 3.42 2.01 349
BTX + STF

5a) Did you take pain medications in the LAST 7 DAYS? Sum 6.31 Sum 7.32 Sum 7.12 Sum 7.26

YES NO
If YES, please clarify which medicine(s): Supplemental Table 1: BTX, botulinum toxin; L, left; NA, not applicable; R, right; SD, standard deviation; STF,
soft-tissue filler; VAS, visual analogue scale.
a Asymmetric facial sensitivity was based on the patient’s own subjective assessment.
5b) I feel I have some form of pain now that requires frequent medication.

YES NO

If YES, please clarify frequency of medication use:

Not every day ! 5 to 6 times per day
1 to 2 times per day ! more than 6 times per day
3 to 4 times per day

SIGNATURE: . . . . . . . . . . . . . . . . . . . . . . . . (all patient data will remain anonymous)!

116 chapter 6 117

 07
Combined Aesthetic
Anterventions for
Prevention of Facial
Ageing, and Restoration
and Beautification
of Face and Body.

Last author. Impact Factor 2.516, SJR 1.157

Published in Journal of Clinical, Cosmetic Investigational Dermatology. 2017 Oct 30;10:423-429. doi: 10.2147/CCID.S144282.
Original publisher: Dove Medical Press

Fabi S1, Pavicic T2, Braz A 3, Green JB4,5, Seo K6, van Loghem JAJ7.

1. Cosmetic Laser Dermatology, San Diego, CA, USA.

2. Private Practice for Dermatology and Aesthetics, Munich, Germany
3. Division of the Policlínica Geral do Rio de Janeiro (PGRJ), Rio de Janeiro, Brazil
4. Skin Associates of South Florida, Miami, FL, USA
5. University of Miami Department of Dermatology, Miami, FL, USA
6. Seoul National University, Seoul, South Korea
7. Depertment of Ophthalmology, Academic Medical Center, University of Amsterdam,
Amsterdam, The Netherlands. UMA Institute private practice, Amsterdam, Netherlands

118 chapter 7 119

 abstract
The Merz Institute of Advanced Aesthetics Expert Summit focused on patients’ desires for natural-looking rejuvenation
was held in Prague, Czech Republic, from 19–20 and how this requires a three-dimensional approach
November 2016. The meeting had a distinct advisory board combining products that relax the musculature, volumize,
character and invited aesthetic practitioners from all over and re-drape the skin. Besides treating the aging face, these
the world to hear an international faculty present a range procedures are increasingly used to enhance facial features
of keynote lectures and conduct live injection sessions as well as to delay facial aging in younger patients. The
with an emphasis on recent developments in combination presentations covered patients from different ethnicities as
aesthetic interventions for face and body rejuvenation and well as the treatment of non-facial areas, with a particular
beautification. Aging is associated with changes in bones, focus on the use of Ultherapy® for skin lifting and
muscles, ligaments, adipose tissue, and skin and, moreover, tightening, and new aesthetic procedures such as Cellfina®
involves interactions among these tissue types. To achieve and diluted Radiesse®. The current report provides a
the most natural and harmonious rejuvenation of the face, summary of key presentations from the meeting.
all changes that result from the aging process should be
corrected, which generally involves treatment with more
Keywords
than a single agent or technology. Presentations described
calcium hydroxylapatite, Cellfina, hyaluronic acid,
innovative treatment algorithms for the face and body and
incobotulinumtoxinA, Ultherapy

120 chapter 7 121

 introduction
More than 400 experts in dermatology, plastic surgery, and aesthetic medicine from 60 countries gathered in Prague Drs Fabi and Kate Goldie (European Medical Aesthetics Ltd, London, UK) reviewed recently published consensus
to participate in the Merz Expert Summit on combined aesthetic interventions for the face and body. This was recommendations for combined aesthetic interventions,2,3 which are the first guidelines published to date to provide
an interactive event with a bidirectional transfer of knowledge combining many medical specialties. To stimulate specific recommendations for the optimal combination, treatment timing, and sequence with botulinum toxin (eg,
participation from this broad international audience, simultaneous translations from English into six languages (French, incobotulinumtoxinA; Xeomin®/Bocouture®; Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany), calcium
German, Italian, Portuguese, Russian, and Spanish) were provided. hydroxylapatite (CaHA; Radiesse®), and hyaluronic acid (HA) fillers (eg, Cohesive Polydensified Matrix [CPM] HA
fillers; Belotero®; Anteis S.A, Geneva, Switzerland), and microfocused ultrasound with visualization (Ultherapy®) for
The aim of the meeting was to inform physicians about recent advances in aesthetic medicine with a focus on early intervention and aesthetic restoration of the face as well as other areas of the body.
combined interventions, and to gain audience feedback about their experience and usual practices. Over the course
of 2 days, 20 sessions took place covering a range of topics including: combining aesthetic interventions for the In terms of the sequence of multiple treatments in one area, there was strong consensus to consider spacing
prevention and rejuvenation of aged skin, multicultural aspects in the perception of beauty and patient expectations, individual treatments by 1–2 weeks to allow resolution of local side effects and/or to assess the results; however, if
treatment options for non-facial areas, and emerging procedures for body beautification and rejuvenation such as undertaken on the same day, incobotulinumtoxinA, CPM-HA, and/or CaHA may be performed in any sequence.
Cellfina®, Ultherapy®, and diluted Radiesse® (calcium hydroxylapatite, CaHA) (all three from Merz North America, For combination therapy with multiple agents on the same day, Ultherapy® should be performed before the filler
Inc., Raleigh, NC, USA). or incobotulinumtoxinA.2

Combined aesthetic interventions have widespread application in clinical practice, but results are infrequently The consensus presents the order and sequence for early intervention and restoration of the upper face, midface, and
reported at scientific meetings and in the medical literature, as the area is difficult to study; existing reports are mainly lower face.2 In the upper face, incobotulinumtoxinA is recommended for muscle control; for patients presenting with
anecdotal. Many of the speakers reminded the audience to look beyond the face and consider the neck, décolletage, volume depletion of the forehead and temples, the recommendation is to start with an HA. In the midface, CPM-HA
and the hands. Body rejuvenation procedures for the buttocks, thighs, arms, and abdomen were also reviewed. and/or CaHA are recommended for volume loss in the cheek without laxity; however, in the presence of laxity, the
This report summarizes presentations from the meeting on recent developments in combined aesthetic consensus recommends starting with Ultherapy® followed by CPM-HA and/or CaHA. In the lower face, combination
interventions, including which treatments to undertake first and which to combine to provide patients with the best treatment using incobotulinumtoxinA to relax any areas being pulled down, and CPM-HA and/or CaHA to create
possible outcomes. structure and volume, is recommended. For the neck, incobotulinumtoxinA is recommended as first-line treatment,
followed by Ultherapy® and low-viscosity CPM-HA and/or diluted CaHA as second- and third-line treatments,
respectively, to stimulate neocollagenesis and improve skin texture.3 For the décolletage, low-viscosity CPM-HA and/
Rationale for combined aesthetic interventions or diluted CaHA to stimulate neocollagenesis are recommended for early intervention. However, in cases of true
restoration, Ultherapy® is recommended as first-line treatment followed by low-viscosity CPM-HA and/or diluted
For the most natural and harmonious rejuvenation of the face, all changes that result from the aging process should CaHA on the same day.
be corrected. Dr Tatjana Pavicic (Private Practice, Munich, Germany) reminded the audience that aging is a result of
the interplay of changes occurring in all five facial anatomical layers: skeleton, ligaments, muscles, adipose tissue,
and skin. To target these, multilayer, combined intervention is required to relax, volumize, resurface, and re-drape Combined measures for prevention of facial skin aging
facial skin.
Facial skin aging is caused by intrinsic and extrinsic mechanisms. Intrinsic skin aging represents the normal course of
No single technology, filler, or neuromodulator can achieve all the results desired in treating the aging face. The aging for all tissues, whereas extrinsic aging is mainly caused by exposure to UV radiation, pollution, and cigarette
question is when and how to combine different aesthetic interventions safely and effectively for the face, hands, neck, smoking that is superimposed on intrinsic skin aging. Exposed areas of the body such as the face are, therefore,
and décolletage. subjected to both types of skin aging. Dr André Braz (Policlínica Geral do Rio de Janeiro, Rio de Janeiro, Brazil)
presented his case studies, demonstrating treatment recommendations for prevention in individuals with no or
minimal signs of aging from a consensus meeting involving 14 specialists in aesthetic medicine that took place in April
Tips and techniques for combined aesthetic interventions 2016 in Monaco.4 Skin glow and skin texture have a significant impact on attractiveness. Healthy skin can be retained
with the use of topical skincare products, including daily UV protection, moisturizers, and topical antioxidants. These
Dr Sabrina Fabi (Cosmetic Laser Dermatology, San Diego, CA, USA) described how combined aesthetic interventions will also prevent further damage in patients presenting with environmentally induced irregular pigmentation. For the
are more than just the sum of the components. Optimal outcomes are dependent upon choosing the appropriate tool prevention or early treatment of superficial skin laxity and/or fine wrinkles, options would include topical skincare
and ensuring that it is used correctly. A deep understanding of product characteristics, anatomy, and the physiology of (eg, UV protection, antioxidants, retinoids, moisturizers, DNA repair enzymes), smoking abstinence or cessation, and
aging is essential to know when, where, and how to use different modalities to provide facial harmony. some device-based rejuvenating procedures (eg, intense pulsed light, radiofrequency).

Live injection sessions throughout the 2-day meeting illustrated some of the injection techniques that can be For patients presenting with early static lines and folds (≤grade 2 on contraction and ≤grade 1 at rest on assessment
used when combining aesthetic interventions, with a strong emphasis on safety. Physician experience is essential scales), the consensus recommended preventative injections with incobotulinumtoxinA. Soft-tissue fillers are
for satisfied patients and, as pointed out by Dr Jani van Loghem (Doctors Inc. / UMA Institute, Amsterdam, The recommended for patients with laxity of deep fibrous structures to provide support. Ultherapy® and radiofrequency
Netherlands), ongoing training is essential for all levels of professionals to ensure safety and avoid complications as may also be used in areas demonstrating laxity. Early intervention with fillers is recommended in individuals with
well as achieve the best outcomes for patients.1 facial volume loss that is asymmetric or in patients without strong bony support.

122 chapter 7 123

 Combined measures for beautification: different ethnicities, different approaches Furthermore, recommendations were provided to help avoid adverse events related to the device. The most
commonly reported adverse event associated with MFU-V is brief discomfort during the treatment session. A
To date, most studies and published recommendations on the use of aesthetic interventions (especially their use in combination of topical anesthesia and oral analgesics (eg, 2x 400 mg ibuprofen) are routinely used prior to treatment
combination) are based on Caucasian populations. However, individuals from different ethnic backgrounds vary to reduce pain levels. The quality of coupling/contact and the amount of ultrasound gel used can affect whether
in both facial appearance and baseline structural facial anatomy. These factors must be taken into account when energy is being efficiently delivered at the appropriate depth. Excess ultrasound gel can result in welts on the skin
planning a treatment approach.5,6 surface due to energy delivery at superficial depths (Figure 1). Dermal papules can arise following pulse stacking
(ie, repeated delivery of energy to the same location). Visualization combined with a detailed knowledge of local
Dr Kyle Seo (Seoul National University Hospital, Seoul, South Korea) presented his perspective on ethnic differences, anatomy should be used to avoid delivering energy to facial nerves, which can result in neuropraxia.
with a focus on East Asian patients. The Asian face is typically wider and flatter compared with the narrower
Caucasian face. The use of botulinum toxin to counteract masseter hypertrophy, temporalis hypertrophy, and parotid
gland enlargement – all of which contribute to the wide face that is characteristic of Asian patients – is a popular
indication to make the face slimmer and appear more oval. Asian patients typically require lower doses of toxin
than Caucasian patients (8–12 U for glabella and 3–6 U for horizontal forehead lines), probably because their facial
muscles are less active and, therefore, develop fewer mimetic lines – a characteristic that could be race- or culture-
related. In addition, Asian people have a shorter corrugator muscle and thicker skin than Caucasian people. A
further popular indication for botulinum toxin in Asia is for body reshaping, particularly slimming of the calf, deltoid,
trapezius, and quadriceps femoris muscles to create a smoother, slimmer, and elongated body contour.

The use of fillers to add volume to the vertical midface, including the forehead, nose, sunken cheeks, and chin is also
widely indicated in Asians to produce a slimmer and more three-dimensional face, and is useful not only for facial
rejuvenation, but also for beautification through the enhancement of facial contours. In contrast, horizontal midface
augmentation such as accentuating the cheek bones, popular in Caucasian patients, would only make an Asian face
look wider and should be avoided. It should be noted that the nose is a challenging part of the face to inject, even in
experienced hands, because of the risk of accidental intravascular injection, particularly in individuals whose vascular
anatomy has altered (eg, after rhinoplasty). Figure 1
Transient welts following Ultherapy ® as a result of application of excess gel and their resolution 3 weeks
The focus of Dr Braz was on Latin American beauty, where the main features are a well-defined lower face with a later (Courtesy of Dr Sabrina Fabi).
clear jawline, a wide midface, and a feminine body. He illustrated how the CPM-HA range can be used to achieve
this facial beauty concept in a global face approach through treatment of volume depletion and modeling of facial
contours. Target areas included the cheek, tear trough, temporal hollows, chin, and nasal dorsum. With the use of
injection videos, cadaver dissections, and skulls, he illustrated the precise anatomy of each injection area, and how Ultherapy® has been studied for skin tightening/lifting in multiple areas, including the décolletage,7,8 buttocks,9
this defines the correct layer of injection, and selected injection techniques to efficiently and safely augment the knees,10,11 medial thighs,10 arms/elbows,10,12 and the abdomen.13 Figure 2 illustrates the use of this technique for
different regions of the face. skin tightening on the buttocks. Dr Fabi emphasized that achieving the patient’s aesthetic goals may require the
combination of Ultherapy® with other aesthetic treatments (eg, filler and toxin injections, liposuction, cryolipolysis).
Merz is currently developing a series of scales, specifically for guiding aesthetic interventions and assessing treatment The use of Ultherapy® to treat skin laxity on the body is an area that is still being actively researched. Dr Fabi is
outcomes in Asian patients. Examples are the facial shape scales, which categorize faces as predominantly oval, investigating Ultherapy® for the treatment of abdominal laxity in a study that aims to enroll 24 subjects to receive two
oblong, round, or square, and the calf scales, which are intended to provide guidance for calf-slimming procedures. treatments 90 days apart (700 lines per abdomen at both the 3 and 1.5 mm depths).

Ultherapy® – face and beyond

Ultherapy® was developed to meet the growing public demand for noninvasive skin lifting and tightening procedures.
The device combines microfocused ultrasound (MFU) with high-resolution ultrasound imaging to allow the user
to visualize where the MFU energy will be applied. Use of ultrasound visualization to target the correct tissues is
essential as there are patient variations in skin thickness and anatomical features (on the basis of gender, age, body
weight, ethnicity, etc). Visualization is the only way to select the appropriate treatment depth and transducer. Dr Fabi
recommended the use of two transducer depths for synergistic effects, but highlighted the importance of ensuring that
both depths are appropriate using visualization.

124 chapter 7 125

 A
Emerging body beautification and rejuvenation procedures

Cellulite – the Cellfina® system

Cellulite affects the vast majority of women, even those who are fit and slim, but a better understanding of its
pathophysiology has led to the development of the only long-term treatment cleared by the US FDA for cellulite
treatment. Dr Jeremy Green (Skin Associates of South Florida, Miami, and University of Miami Department of
Dermatology, FL, USA) introduced the Cellfina® system (Merz North America, Inc.), which has been engineered to
treat cellulite by addressing the underlying physical structures that cause the appearance of dimples. Imaging and
microscopy analyses have shown that fibrous septae oriented perpendicular to the skin surface connect the dermis
with deeper fascial layers. Cellulite on the thighs and buttocks arises when these septae pull the undersurface of
the skin causing dimpling with protrusion of the superficial fat compartments. This results in a tufted or mattress-
like appearance of the skin. Cellfina® targets the release of fibrous septae that cause the appearance of dimples.
The vacuum-assisted tissue stabilization platform enables minimally invasive subcision of the fibrous septae to be
undertaken at one of two controlled depths (6 or 10 mm). The precise targeting and depth control afforded by the
Cellfina® system distinguishes it from manual subcision, which is associated with greater posttreatment morbidity.
Figure 3 illustrates the results of Cellfina® at 5 months posttreatment.

A B

B C

Figure 3
A: Before and B: after photos of Cellfina® treatment in a 50-year old woman
(Courtesy of Dr Jeremy B Green).

Dr Green highlighted the results of the Cellfina® pivotal trial that led to the US FDA clearance of the device for
long-term cellulite treatment. The pivotal study enrolled 55 subjects who were followed for 3 years after a single
treatment.14 On a 5-point cellulite severity scale, the mean improvement was 2 points at 1, 2, and 3 years after the
initial procedure. The proportion of subjects with at least a 1-point improvement in cellulite severity remained at 91%
after 3 years, and subject satisfaction was ≥93% at 1, 2, and 3 years posttreatment. No serious adverse events were
observed, with most subjects reporting only expected treatment-related effects (eg, bruising, induration).
Figure 2 In addition, Dr Green summarized findings from a real-world registry study on patients receiving Cellfina® treatment
A: Ultherapy® buttock treatment map. B: Before treatment. C: 180 days post-treatment. (CRUISE). The study has enrolled 52 patients and collected data on the procedure itself (eg, time to complete
(Courtesy of Dr sabrina Fabi). procedure), patient-reported pain scores, adverse events, and quality of life, and found that the successful results of
the pivotal trial did, in fact, translate into clinical practice.

126 chapter 7 127

 Diluted calcium hydroxylapatite Diluted CaHA has also been effectively used in the neck and décolletage to improve skin mechanical properties
and stimulate neocollagenesis – a procedure pioneered by Prof. Yana Yutskovskaya (Pacific State Medical University,
The use of diluted CaHA for skin tightening is a novel technique that takes advantage of the biostimulatory properties Vladivostock, Russia). The procedure triggers a two-step process of neocollagenesis, in which collagen type I
of CaHA mediated by its calcium hydroxylapatite microspheres, which have been shown in different histological gradually replaces collagen type III,16 and elastogenesis. The technique employed by Prof Yutskovskaya uses
studies to stimulate neocollagenesis, neoelastogenesis, angiogenesis, and fibroblast proliferation.15,16 This makes it an multiple (0.025 mL per pass), retrograde linear threading (0.5 cm apart) of 1:2–1:6 diluted CaHA (diluted with saline
effective treatment for improving contours and firmness in individuals with age-associated upper arm skin changes. solution, plus lidocaine for pain) placed in the subdermal plane with a needle or cannula, followed by massage with
Drs van Loghem and Valeria Cogorno Wasylkowski (Clinic Novosalud, Madrid, Spain) illustrated a skintightening gel or cream. With this procedure, bruising is virtually unseen. Prof Yutskovskaya stated that she has carried out
procedure in a live demonstration of upper arm and elbow rejuvenation in a female patient. The solution mix this mesotherapy technique combined with Ultherapy® for more than 2 years, and it is now the top procedure at
comprised 3 mL CaHA, 8 mL saline, and 1 mL lidocaine solution. Dr van Loghem demonstrated two different her clinic.
techniques. In the right arm, he used four entry points in the upper and lower peripheries of the anterior brachial
zone and injected diluted CaHA subdermally with a 5 cm-long 25G cannula using a crosshatching technique with
retrograde linear threads (Figure 4A). In the left arm, he illustrated a vertical retrograde linear threading technique Hand rejuvenation with calcium hydroxylapatite®
with a 28G needle using multiple entry points (Figure 4B). This approach is faster than with the cannula, but may
cause more bruising. Photos before and after treatment with CaHA for the upper arm are shown in Figure 4C and Hands: exploring injectable treatment options and techniques
D. Dr Cogorno Wasylkowski used a 25G needle and demonstrated the vectoring technique for treatment of the In addition to the face, neck, and décolletage, it is also important not to forget other exposed areas of the body such
right posterior arm, as described previously in detail.17 The approach has achieved good results with a duration of as the hands. Hands can give away a person’s age as easily as the face.18
approximately 1 year, depending on the degree of skin laxity. Optimal results can be expected at 3–4 months. CaHA is the first and currently only dermal filler approved by the US FDA to correct volume loss in the hands. In a
recent multicenter, randomized, controlled, single-blinded study, treatment has been shown to have a duration of
effect of at least 12 months following a single procedure and is very well tolerated, with adverse events restricted to
A B
mild to moderate injection site reactions and without issues relating to hand function.19
The correct depth of injection when treating the hand is in the subdermal plane and not in the tendinous layer. One
technique to achieve this was explained and demonstrated by Dr Pavicic. The Skin Scraping Threading Technique
(SSTT®) for hand augmentation places filler in the undersurface of the dermis (the dorsal superficial lamina).20 The
SSTT® was developed to allow safe and accurate injection of filler by “scraping at the bottom of the dermis” with a
cannula. Using this technique, filler placement is restricted to the fascial layer and should be performed with a 7-cm
long, non-flexible cannula (22G 2 3/4”) and a proximal insertion point. The filler is injected with the cannula bevel
facing upwards.

C D

Figure 4
Upper arm injection techniques with diluted calcium hydroxylapatite for skin tightening. A: Crosshatching
technique with retrograde linear-threads performed with a 5 cm-long 25G cannula. B: vertical retrograde
linear threading technique performed with a 28G needle. C: Before and D: after treatment with CaHA for the
upper arms (Courtesy of Dr Jani van Loghem).

128 chapter 7 129

 conclusion references
With our increased understanding of facial anatomy and new and refined uses for different aesthetic tools and 1. Van Loghem JA, Humzah D, Kerscher M. Cannula versus 11. Gold MH, Sensing W, Biron J. Use of micro-focused
products, the spectrum of facial aesthetics is constantly evolving. A clear message from this expert summit was that, to sharp needle for placement of soft tissue fillers: an ultrasound with visualization to lift and tighten lax knee
offer patients the best possible outcomes, we should no longer think about individual treatments but look at the whole observational cadaver study. Aesthet Surg J. Epub 2016 skin (1.). J Cosmet Laser Ther. 2014;16(5):225–229.
face and at different tissue depths to determine the appropriate treatment approach. Recognizing that more than one Dec 16. 12. Rokhsar C, Schnebelen W, West A, Hornfeldt C. Safety
procedure will be required to correct all the issues, injectables and other modalities such as topical skincare and 2. Carruthers J, Burgess C, Day D, et al. Consensus and efficacy of microfocused ultrasound in tightening of
energy-based therapies can be combined for optimal results. In addition to rejuvenation, physicians also have the right recommendations for combined aesthetic interventions in lax elbow skin. Dermatol Surg. 2015;41(7):821–826.
tools in their hands to prevent or delay skin aging, which can be offered to the increasing numbers of younger patients the face using botulinum toxin, fillers, and energy-based 13. Sasaki HG, Tevez A. Microfocused ultrasound for
visiting aesthetic practices. devices. Dermatol Surg. 2016;42(5):586–597. nonablative skin and subdermal tightening to the
3. Fabi SG, Burgess C, Carruthers A, et al. Consensus periorbitum and body sites: preliminary report on
The meeting also highlighted that an understanding of different global concepts of beauty is essential for achieving recommendations for combined aesthetic interventions eighty-two patients. J Cosmet Dermatol Sci Appl.
optimal outcomes. In each ethnic group, the best outcomes are obtained by maximizing a patient’s good structural using botulinum toxin, fillers, and microfocused 2012;2(2A):108–116.
characteristics and improving structural deficiencies common to that group. ultrasound in the neck, décolletage, hands, and other 14. Kaminer MS, Coleman WP 3rd, Weiss RA, Robinson DM,
areas of the body. Dermatol Surg. 2016;42(10):1199– Grossman J. A multicenter pivotal study to evaluate tissue
The focus of the meeting was not only the face, with many of the speakers reminding the audience to consider other 1208. stabilized-guided subcision using the Cellfina device for
areas that can give away a person’s age including the neck, décolletage, and the hands. Furthermore, with emerging 4. Landau M, Anand CV, Besins T, et al. First consensus on the treatment of cellulite with 3-year follow-up. Dermatol
procedures such as Cellfina® for cellulite, and Ultherapy® and diluted CaHA for skin tightening and improving skin primary prevention and early intervention in aesthetic Surg. Epub 2017 Jun 28.
mechanical properties, the Merz Aesthetics portfolio has been broadened to provide innovative approaches for body medicine. J Drugs Dermatol. 2017;16(9):846–854. 15. Yutskovskaya YA, Kogan EA. Improved neocollagenesis
rejuvenation and beautification. 5. Rho NK, Chang YY, Chao YY, et al. Consensus and skin mechanical properties after injection of diluted
recommendations for optimal augmentation of the Asian calcium hydroxylapatite in the neck and décolletage: a
face with hyaluronic acid and calcium hydroxylapatite pilot study. J Drugs Dermatol. 2017;16(1):68–74.
Acknowledgments fillers. Plast Reconstr Surg. 2015;136(5):940–956. 16. Yutskovskaya Y, Kogan E, Leshunov E. A randomized,
6. Sundaram H, Huang PH, Hsu NJ, et al; Pan-Asian split-face, histomorphologic study comparing a volumetric
The authors thank all speakers for contributing to the content of the Expert Summit, and Jenny Grice for editorial Aesthetics Toxin Consensus Group. Aesthetic applications calcium hydroxylapatite and a hyaluronic acid-based
assistance, which was funded by Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany. of botulinum toxin A in Asians: an international, dermal filler. J Drugs Dermatol. 2014;13(9):1047–1052.
multidisciplinary, Pan-Asian consensus. Plast Reconstr 17. Cogorno Wasylkowski V. Body vectoring technique
Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany, supported the Expert Summit and the writing of these Surg Glob Open. 2016;4(12):e872. with Radiesse(®) for tightening of the abdomen, thighs,
proceedings. The content of the publication reflects the experts’ independent opinions and experiences. Merz 7. Fabi SG, Massaki A, Eimpunth S, Pogoda J, Goldman MP. and brachial zone. Clin Cosmet Investig Dermatol.
Pharmaceuticals GmbH does not encourage or endorse the use of any product manufactured or distributed by the Evaluation of microfocused ultrasound with visualization 2015;8:267–273.
company in ways that are not approved by applicable notified bodies or regulatory agencies. for lifting, tightening, and wrinkle reduction of the 18. Bains RD, Thorpe H, Southern S. Hand aging: patients’
décolletage. J Am Acad Dermatol. 2013;69(6): 965–971. opinions. Plast Reconstr Surg. 2006;117(7):2212–2218.
8. Fabi SG, Goldman MP, Dayan SH, Gold MH, Kilmer 19. Goldman MP, Moradi A, Gold MH, et al. Calcium
Disclosure SL, Hornfeldt CS. A prospective multicenter pilot study hydroxylapatite dermal filler for treatment of dorsal
of the safety and efficacy of microfocused ultrasound hand volume loss: results from a 12-month, multicenter,
The authors have disclosed financial relationships with the following companies: with visualization for improving lines and wrinkles of the randomized, blinded trial. Dermatol Surg. Epub 2017 May
S Fabi has conducted research for Allergan, Galderma, Merz, Alastin, Colorscience, Valeant, and Revance, is a décolleté. Dermatol Surg. 2015;41(3):327–335. 25.
speaker for Allergan, Galderma, Merz, and Valeant, and a consultant/advisory board member for Allergan, Galderma, 9. Goldberg DJ, Hornfeldt CS. Safety and efficacy of 20. Lefebvre-Vilardebo M, Trevidic P, Moradi A, Busso M,
Merz, and Valeant. microfocused ultrasound to lift, tighten, and smooth the Sutton AB, Bucay VW. Hand: clinical anatomy and
T Pavicic has received honoraria from Merz Aesthetics and Galderma Pharma SA for speaker activities. She is a buttocks. Dermatol Surg. 2014;40(10):1113–1117. regional approaches with injectable fillers. Plast Reconstr
consultant for Merz Aesthetics and Galderma Pharma SA and serves on advisory boards for these companies. 10. Alster TS, Tanzi EL. Noninvasive lifting of arm, thigh, and Surg. 2015;136(5 Suppl):258S–275S.
A Braz is a consultant and speaker for Allergan, Galderma, Merz, and Palomar. knee skin with transcutaneous intense focused ultrasound.
JB Green is an advisory board member, research investigator and speaker for Allergan, Galderma, and Merz, an Dermatol Surg. 2012;38(5):754–759.
investigator and advisory board member for Sienna and Lutronic, an investigator for Brickell Biotech, Cutera, Valeant,
Teoxane, Revance, and Neothetics, and holds stock in Illustris.
K Seo serves as a clinical investigator and/or consultant for Allergan, Merz Pharmaceuticals, Q-Med/Galderma,
Medytox, LG Life Sciences, and Daewoong.
JAJ van Loghem is a consultant for Merz Aesthetics.

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 08
Complication Management
following Rejuvenation
Procedures with Hyaluronic
Acid Fillers—an Algorithm-
based Approach.

Last author. Impact factor 1.143, SJR 0.599

Published in Plastic and Reconstructive. Surgery Global Open. 2018;6:e2061

This manuscript, has won the

“BEST INTERNATIONAL COLLABORATION - GOLD PAPER” award
in Plastic and Reconstructive Surgery- Global Open for calendar 2018.

Snozzi Ph1, Van Loghem, JAJ2.

1. Smoothline, Bahnhofstrasse Zürich, Switzerland.

2. Depertment of Ophthalmology, Academic Medical Center, University of Amsterdam,
Amsterdam, The Netherlands. UMA Institute private practice, Amsterdam, Netherlands

132 chapter 8 133

 abstract
Background Results
Hyaluronic acid is an ideal facial filler, however, although Algorithms are provided for the most common categories
established as both safe and effective, complications do of complication associated with hyaluronic acid filler
occur. Treatment recommendations that combine both treatment, that is, skin discoloration, edema, nodules,
expert opinions and clinical trial data are currently lacking, infection, and vascular compromise.
partly due to difficulties with diagnoses, nonspecific
diagnostic investigations, and certain disorders presenting Conclusions
with similar symptoms, thereby confounding diagnosis These guidelines are not intended to be complete
and treatment. or exhaustive but may prove informative for aesthetic
clinicians who are responsible for treating patients with
Methods hyaluronic acid fillers. It may help to guide them on
The purpose of this article was to provide the aesthetic recognizing potential complications and it provides clear
clinician with practical recommendations regarding guidance on optimum treatment pathways.
complication diagnosis arising as a consequence of (Plast Reconstr Surg Glob Open 2018;6:e2061;
hyaluronic acid filler rejuvenation treatment. It also doi: 10.1097/GOX.0000000000002061;
provides recommendations for their management using Published online 17 December 2018.)
step-wise treatment algorithms that are based on published
expert opinions, as well as the author’s clinical experience.

134 chapter 8 135

 background complication management
Hyaluronic acid (HA) is a common, naturally occurring linear polysaccharide found in skin and tissues where one Skin Discoloration
of its functions is a lubricant and moisturizer due to its hydrophilic properties. It shows neither species nor tissue
specificity and does not tend to cause immunologic reactions. These properties make HA an ideal facial filler. Significant skin discoloration can occur at the site of treatment, which is usually self-limiting and usually resolves
However, it has a short half-life, so manufacturers have altered its chemistry by crosslinking chains to retard natural within a few weeks. The main categories of skin discoloration complications include hematoma/ecchymosis (bruising),
degradation. The result is the creation of filler products that reduce the signs of aging by producing natural, healthy neovascularization, hyperpigmentation, and the Tyndall effect/brightening. Ischemia will be discussed later (see
looking features with a product that is well-tolerat- ed, nonimmunogenic and longer lasting.1 Vascular Compromise section). Each of these complications has differing times to onset, clinical presentation, and
differential diagnoses (Fig. 1).
HA fillers are established as safe and effective for facial rejuvenation and they are appealing because they provide an
immediate aesthetic effect. Treatment is reversible, injections can be administered as out-patients and recovery time
is short. Use of HA fillers has increased markedly in recent years, reaching >3 million worldwide in 2017.2 Statistics
compiled by The American Society for Aesthetic Plastic Surgery show HA fillers ranked second for nonsurgical Skin Discoloration (Differential Diagnosis)
procedures performed in 2017 in the United States (722,394 procedures). This is an increase of 2.9% compared with
2016 and an increase of 85% compared with 2012.3
Tyndall -Effect / Skin
Diagnosis Hematoma Neovascularisation Hyperpigmentation Ischemia
brightening
Adverse effects associated with HA filler treatment are uncommon, but they do occur. However, providing
4

recommendations for treating filler complications poses several problems. Although millions of filler treatments are Time of
- Within minutes to hours - Within days to weeks - Within days to weeks - Within days
performed every year, most recommendations regarding complications are based on expert opinions, with little occurrence

data available from controlled studies. This is because clinical trials are difficult to conduct since patients are usually
- Deep hematoma may
treated in private practices, and patients generally demand fast treatment and recovery, without the burden associated appear as a subacute
swelling, with no visible
- Telangiectasia days to
weeks after intradermal
- Post-inflammatory
hyperpigmentation
Clinical - Blue coloration / lighter
with a clinical study. Also, diagnoses are usually based solely on the clinical presentation, with further investigations presentation -
bruises
Temporary or permanent -
filler treatment
Often in the upper
- Especially with
Fitzpatrick skin types IV -
skin

(eg, biopsy, bacteriology) being difficult or nonspecific (eg, general laboratory tests). Furthermore, certain disorders hemosiderin deposits are
possible
nasolabial fold region VI

can present with similar symptoms, for example, type IV delayed immune reaction versus low-grade infection
associated with biofilm. Each requires different treatments, that is, immunosuppression versus antibiotics, although - Erythema (several
possibilities)
both may have the same medical consequences, that is, granulomatous and fibrotic processes caused by chronic Differential - Ischemia (blue-gray
- Rosacea - Hemosiderin deposits - (Malar) edema
diagnosis phase)
immune stimulation. - Post-inflammatory See Vascular
hyperpigmentation
Compromise Section

The purpose of this article was to provide the aesthetic practitioner with practical recommendations regarding
- Sun protection SP50
- Heparin- or Vit. K - - Mostly self limiting in 3 -
diagnosis of the common complications arising from HA filler treatment, as well as recommendations for their containing ointment 12 months without
- Bleaching agent
Therapy - Chemical peels
- IPL therapy - Hyaluronidase
management. For practical purposes, the differential diagnoses are grouped according to the principal clinical - Hemosiderin deposits: - Laser
-
-
IPL (skin type I-IV)
Nd:YAG laser (Skin type
Thioglycolic acid, or laser - IPL
finding and the therapeutic approaches outlined in the step-wise treatment algorithms are based on published expert V-VI)

opinions, as well clinical experience of the authors. These guidelines are not intended to be complete or exhaustive
but should be regarded as a basis for treatment and discussion by aesthetic clinicians. - Apply immediate
compression when - By placing fillers only - By placing fillers only - Selecting the right
Prophylaxis visible bleeding is seen subcutaneous (cannula) subcutaneous (cannula) hyaluronan filler
- Use blunt cannulas - Increased risk in rosacea - Beware skin type - Avoid too superficial
- Beware of patients using patients possible Fitzpatrick V / VI placement of filler
oral anti -coagulants

Figure 1
Skin discoloration (differential diagnosis).

Ecchymosis (bruising) is the most common localized event and can occur in up to 68% of patients.5 Formation of
a larger hematoma is less common but can occur within minutes or hours due to inadvertent laceration of facial
blood vessels. Rather than forming a bruise, if blood beneath the superficial fascia becomes trapped, a firm mass
can appear. To avoid hematoma formation, compression should be applied immediately when bleeding is seen.
Blunt cannulas can be considered, but caution should be used when treating patients taking oral anticoagulants. A
hematoma usually resolves spontaneously over several weeks, but rarely a palpable nodule due to fibrosis of the
hematoma may persist.

When there is evidence of a hematoma, compression for a few minutes is advised. Recommended treatment
comprises vitamin K ointment BID for 7 days, or intense pulsed light therapy.6,7 If there is persistent hemosiderin
staining, pulsed-dye or potassium titanyl phosphate (KTP) laser treatment is recommended.

136 chapter 8 137

 Neovascularization occurs when tiny new blood vessels form at the site of dermal filler injection. Potential Edema
pathophysiological mechanisms are tissue trauma, direct stimulation of angiogenesis through HA breakdown
products,8 or, in the case of telangiectasia, dilatation of tiny dermal veins due to increased tissue pressure after A variety of edema types can occur following facial filler treatment: immediate postinterventional edema, histamine-
intradermal filler injection. Neovascularization can occur days or weeks after the procedure but should fade within mediated edema [eg, physical urticaria, immediate type allergy (type I, IgE-mediated), malar edema, and delayed type
3–12 months without treatment. Intense pulsed light and lasers are effective if erythema or telangiectasias do not allergy (type IV, cell-mediated)]. These vary in time to occurrence and clinical presentation, and treatment options
show spontaneous improvement, with the choice of laser being dependent upon the size of the vessel.9 vary depending upon category (Fig. 3).

Postinflammatory hyperpigmentation has also been reported following HA treatment, with Fitzpatrick skin types IV-VI
being more prone to such events.10,11 However, it is important to distinguish postinflammatory hyperpigmentation
from hemosiderin staining following ecchymosis. Treatment comprises topical retinol, tretinoin, and hydroquinone, or Edema (Differential Diagnosis)
intense pulsed light and laser therapy in persistent cases.

Post-interventional Immediate type Delayed type allergy

Bluish coloration or brightening effects of the skin can occur if HA is injected too superficially or in areas where the Diagnosis
edema
Malar edema
allergy (type I) (type IV)
Acute Infection, LIRS

overlying skin is thin, such as the tear trough area. This phenomenon, known as the Tyndall effect, is due to partial
absorption of red light and reflection of shorter wavelength light (eg, blue) due to the optic chamber that is formed by Time of
- Within hours - Within days - Within minutes to hours - Within days
occurrence
a deposition of HA. Hyaluronidase is the recommended treatment1,9 (Fig. 2).
- Edema, erythema, - Induration, erythema,
- Edema without
pruritus edema, nodules
inflammatory signs (with - Malar Edema after tear
- Local or generalized - Appearance: between 1
Clinical the exception of slight trough treatment, or
swelling of the face day (already sensitized)
presentation erythema) treatment of the
- Urticaria to several weeks
- Maximum 24 -48 hours midface
- Beware of two -phased (sensitizing phase is 5 -7
after treatment

Skin Discoloration (Algorithm) course days)

- Infection
- Overcorrection - Physical urticaria - Transition into a chronic
Differential - Type I – allergy - Hereditary or acquired granulomatous reaction
- Physical u rticaria - Overcorrection angloedema through permanent
Tyndall - Effect / Skin diagnosis immune stimulation may
Hematoma Neovascularisation Hyperpigmentation - Hereditary or acquired - Postinterventional See Sections on
brightening angloedema edema be possible (see section Nodules and
on nodules) Infections

When a hematoma
is seen compression - Cooling
- Keep head in elevated - Cooling
- Keep head in elevated - Prednisone
for a few minutes is Therapy position at night - Antihistamine
position at night - Hyaluronidase
advised - Hyaluronidase - Prednisone
- Bromelain

- Heparin or vit.K -ointment If possible wait for 3 -12 months

- Split the treatment over - No superficial injections - Take caution with - Take caution with
BID for 7 days for neovascularization to subside - Sun protection SPF 50 Hyaluronidase
multiple sessions in the area of the malar patients with a history patients with a history
- IPL spontaneously - Topical hydroquinone
- Patients with rosacea septum an "allergic reaction” to an "allergic reaction” to
(2-% -8%) und Retin -A Prophylaxis - Beware of personal or
have an increased risk of hyaluronic acid hyaluronic acid
(tretinoin 0,1%) erythema / edema after family history of malar - In unclear cases: perform - In unclear cases: perform
the treatment edema a skin test a skin test

Persistence of Lack of
hemosiderin improvement Lack of Figure 3
improvement
within 3 months
Edema (differential diagnosis)

- Skin type I -IV: IPL

Topical thioglycolic acid once
Laser Laser / IPL - Skin type V -VI: Nd:YAG -
every 2 weeks for 2 -3 months
Laser

Short-term immediate postintervention edema comprising transient swelling is normal and common to all dermal
Figure 2 fillers. It is related to injection volume and technique and usually disappears within 1 week.9 Generally, no treatment
Skin discoloration (algorithm). is required, but in severe or persistent cases, bromelain can be prescribed.12

Some patients may develop histamine-mediated edema, either through direct release of histamine in physical urticaria
or through IgE-mediated antibody response from hypersensitivity to components of the filler (type I hypersensitivity
reaction). Even though type I hypersensitivity reactions are commonly mentioned in literature,9,13 the authors believe
that most angioedema cases seen soon after HA injections are due to physical urticaria or hereditary or acquired
angioedema, respectively, triggered by mild trauma, rather than IgE-mediated histamine release. Nonetheless, in
rare cases, IgE-mediated antibody response to either the disinfection agent (eg, chlorhexidine) or HA fragments or
other filler components (eg, lidocaine) is possible. Reactions can be severe and long-lasting with either localized or
generalized edema. Treatment depends on the severity, but if there is no spontaneous resolution, antihistamines and
oral corticosteroids are recommended. If angioedema occurs after a substantial period of time from the treatment (eg,

138 chapter 8 139

 months after lip augmentation), it may be due to an acquired angioedema rather than a reaction to the filler itself. Nodules
Malar edema is a serious and long-lasting complication that has been reported with all fillers when injected
into the infraorbital hollow and tear troughs. This region is particularly susceptible to adverse effects due to
compromised lymphatic drainage and effects due to the impermeable barrier of the malar septum and is thus Nodules (Differential Diagnosis)
prone to fluid accumulation.14 Malar edema is difficult to treat, but initial recommendations include lymphatic
Non -inflammatory Inflammatory
drainage and massage, with the head elevated at night.14 In cases of persistent malar edema, hyaluronidase should
Accumulated filler material / Genetic factors Product factors Chronic granulomatous
be administered.9,14 implant nodule
Biofilm possible
reaction
Immunological factors
Diagnosis /
type
Non–antibody-mediated (delayed, type IV) allergic reactions are mediated by T lymphocytes rather than antibodies Late Inflammatory Response Syndrome (LIRS)

and result in induration, erythema, and edema. Potential triggers are the injection needle in cases of nickel allergy,15–18
or possibly HA fragments and other filler components. They may occur as early as 1 day after injection but can be Time of -
-
Usually immediate
Sometimes delayed occurrence due to - After weeks to months, sometime years
occurrence
seen as late as several weeks after injection and may persist for many months. Delayed hypersensitivity reactions are migration of the filler material

nonresponsive to antihistamines and recommended treatment is a short course of oral corticosteroids followed by - Accumulated filler: overcorrection, migration
- Biofilm seems pivotal by inducing a permanent immune response, thus leading to a chronic granulomatous reaction
- Implant nodule: mild foreign body reaction to
administration of hyaluronidase where there is no improvement.9,19 If the reaction commences more than 3 weeks Pathophysiology the filler is physiological; excessive reaction
- Other immunological phenomena may play a role (e.g. excessive foreign body reaction, Type IV reaction, others)
- Occasionally another infection (e.g. flu, gastroenteritis) may precede and trigger LIRS
may lead to a fibrotic, encapsulated implant
after injection, late inflammatory response syndrome (LIRS) should be considered (Fig. 4). nodule
- Product factors and patient factors play a role

- Inflammatory nodules, plaques or seldom cysts

Clinical - All areas where the filler is present may react
- - -
Edema (Algorithm)
Painless, non-sore resistance Inflammatory, tender nodules Histology: Sclerosing, edematous or cystic
presentation granuloma
- Progression of fibrosis over time

Differential - Deep situated hematoma, encapsulated - Fluctuating nodule: abscess

Onset within minutes to hours Onset within days Onset later then 4 weeks
diagnosis hematoma - Sarcoidosis

Concomitant - Accumulated filler material: redistribution by

No Yes Yes Typical malar No Acute infection Yes massage, hyaluronidase - Broad spectrum antibiotics - Hyaluronidase
itch / urticaria /
angioedema? edema? suspected? Therapy - Encapsulated implant nodule: - Hyaluronidase (concurrent with antibiotic - Intra-lesional corticosteroids
intra-lesional corticosteroids often not treatment) - Intra-lesional 5-FU
successful, excision may be required
No

Post-interventional Type I allergy or Type IV allergy Prophylaxis - Avoid overcorrection

- Creating an aseptic environment during treatments!
Malar edema Acute infection LIRS - Avoiding products that seem to be more prone than others to develop a LIRS
edema suspected physical urticaria suspected

Minor Severe
Respir.,
No abdominal or Severe

- Cooling
cardiovascular Observation for Figure 5
sympt.? one week (often Check algorithm Acute Check algorithm
- Bromelain TIS
Minor
spontaneous Infections Nodules Nodules (differential diagnosis)
improvement)
Yes
Lack of
improvement
Anaphylactic reaction
Conservative Lack of
grade II - IV
treatment improvement Nodules, either inflammatory or noninflammatory, can arise from a number of causes, and it is important to establish
Levocetirizin 5mg OD +
-
-
Supine with legs up
BP monitoring
- Keep head a working diagnosis before treatment (Fig. 5).
prednisone 50mg OD for 3 days in elevated
- 0.3 mg epinephrine IM
position at
- 2-4mg clemastin +
night
125mg methyl -
- Massage /
prednisolon IV Prednisone 50mg Deterioration
lymphatic
-
NonInflammatory Nodules
Hospitalization OD for maximum
Lack of drainage
- Monitoring 24hrs 7 days
improvement
Lack of
Lack of improvement Alternative
improvement
within 4 weeks
Noninflammatory nodules may be visible and palpable, particularly in areas where there is thin soft-tissue coverage
Hyaluronidase (eg, eyelids, nasojugal region and lips).20 They occur when too much filler accumulates due to poor technique caused
by overcorrection, superficial filler placement, facial area with significant muscular activity (eg, around the modiolus)
Figure 4 or incorrect filler selection for the anatomical area. These nodules form isolated lumps at the injection site and are
Edema (algorithm) well defined from surrounding tissue.9 Recommended initial treatment is massage to redistribute the filler material,
but expression after puncturing the skin with a large gauge needle (22-18G) or hyaluronidase may be required.
Approximately 30 units of hyaluronidase have been shown to effectively dissolve 0.1 cc of various HA-based fillers;
however, the degree of dissolution is based on the 3-dimensional structure and cross-linking properties of the specific
filler substance, as well as the time period postinjection.21–23

140 chapter 8 141

 Inflammatory Nodules Nodules (Algorithm)
All injected implants cause an initial influx of neutrophils and mononuclear cells24 with phagocytosis by aggregated
Non-inflammatory Inflammatory
macrophages, and activation of fibroblasts with subsequent collagen deposition. A certain foreign body reaction to
HA implants is not only physiological but also desired, since it stimulates the production of several extracellular matrix
components.25 However, if there is a failure of effective phagocytosis or inadequate stimulation of immune cells with
Yes No (multiple)
ongoing macrophage activation, this may lead to a granulomatous and fibrotic process.26 Clinical findings may present Solitary Nodule?
- Hyaluronidase
as multiple red, tender, inflammatory nodules with swelling, erythema, and occasional suppuration.27 Inflammatory - For a superficial, well -
defined lump, incision

Implant nodule suspected

granulomatous processes are characterized by later onset, appearing weeks to months after treatment. and extrusion may be
considered
No Systemic antibiotics
- Redistribution by massage Fluctuating?
with or without injection - Clindamycin 300mg TID + ciprofloxacin
The pathophysiology behind the transition of physiological foreign body reactions into severe inflammatory 500mg BID for 14 days

Biofilm / chronic granulomatous reaction suspected

of saline / lidocaine Severe inflammation / edema
Yes
granulomatous processes is complex and not fully understood, with numerous factors playing a potential role.
Lack of improvement / 24-48 hrs after starting
Different chain lengths of HA components have different effects on macrophage activation28 and bioimplants seem Increase of fibrosis Systemic antibiotics
corticosteroids
to act as T-cell specific activators in individuals with a predisposing genetic background.26 Occasionally, a trivial Concurrent prednisone
50mg OD, max. 7 days Intra - lesional Hyaluronidase
DD abscess, cystic granuloma
infection (influenza or gastroenteritis) may precede a late inflammatory reaction29–33 and it is well-known that IFN- Fibrotic implant nodule Check algorithm Acute
- Breaking up the matrix (biofilm)
- Reduction of the substrate (foreign body
Infections
therapy (eg, in hepatitis C virus [HCV] therapy) may trigger a granulomatous process at sites of filler implants.34,35 reaction)

These findings suggest that reactivity levels of an individual’s immune system play a crucial role.
Lack of improvement

Lack of improvement
Finally, there is abundant evidence that biofilms may be pivotal in triggering late inflammatory reactions. Biofilms that Intra - lesional steroids
- 0,3 ml of 10 mg / ml triamcinolone + 0,2
may be preceded by infection are widespread and comprise densely packed communities of common skin colonizing Steroids often not successful ml 2% lidocaine + 0,5 ml physiologic saline
- 0,1 ml (lips / tear trough) up to 0,5 ml
bacteria (eg, S. epidermidis, P. acnes)36 that self-encapsulate with a complex protective adhesive matrix. This allows (cheeks) per nodule
- Once every 4 weeks
them to irreversibly adhere to living structures or inert surface, so when a filler is injected, it can become coated
with bacteria and forms a biofilm, inducing a permanent immune response that may eventually lead to a chronic Lack of improvement

granulomatous reaction.27,37
Intra- lesional steroids + 5 FU
Lack of improvement - 0,5 ml 50 mg / ml 5 -FU + 0,3 ml 10 mg /
ml triamcinolone + 0,2 ml 2% lidocaine
Recommended treatment is systemic antibiotic therapy, but filler removal is important, so hyaluronidase should be - 0,1 ml (lips/tear trough) up to 0,5 ml
(cheeks) per nodule
used 24–48 hours after commencing antibiotic treatment. In cases of biofilm formation, hyaluronidase will help break Excision - Once every 4 weeks

down the matrix, thus increasing the efficacy of antibiotic therapy, and in direct immunological reaction to the filler,
hyaluronidase will remove the substrate. If inflammation and edema are severe, a short course of oral corticosteroids Figure 6
may prove beneficial. If lesions are unresponsive to antibiotic and hyaluronidase treatment, intralesional Nodules (algorithm)
corticosteroids should be used.9 If lesions are still unresponsive, the addition of 5-FU is recommended.9 Schelke
et al.38 recently demonstrated that material removal with intralesional laser treatment was effective and so may be
considered as another treatment option (Fig. 6).
Infections

As with any procedure that breaks the surface of the skin, dermal filler injections are associated with a risk of
infection.20 It is important to minimize this risk by using thorough antisepsis throughout the procedure. Although
rare, acute resistant postfiller infections can occur, and may be bacterial or viral in nature.9 This article focuses on the
following potential consequences of infections: erysipelas/cellulitis, abscess, herpes simplex, and biofilms (Fig. 7).

142 chapter 8 143

 Reactivation of Herpes simplex is the most common viral infection to occur after filler injection into the lips. Patients
Infections (Differential Diagnosis)
with a history of cold sores or fever blisters may be treated prophylactically with valacyclovir 500mg BID for 3 days. If
the patient has not received prophylactic treatment, but infection is recognized within 24 hours, valaciclovir at a dose
Diagnosis Erysipelas, cellulitis Abscess Herpes lesions Biofilm of 500 mg BID for 5 days is recommended1,9 (Fig. 8).

Time of Subacute
Acute (within days)
occurrence (within weeks to months)

Suspected
-
-
S. pyogenes, S. aureus
When developing later then
-
-
S. aureus
When developing later then - Pseudomonas species, S. Infections (Algorithm)
two weeks after the injection two weeks after the injection - Herpes Simplex Type I epidermidis, P. acnes,
culprit atypical bacteria may be atypical bacteria may be Acinetobacter, others
involved involved
Subacute
Acute (within days)
(within weeks to months)

- Sharp (erysipelas) or non-

sharply defined (cellulitis)
Clinical - Herpes typical vesicles
inflammatory swelling - Like cellulitis, but with a
- Sometimes Erysipelas, cellulitis Abscess Herpes lesions Biofilm
presentation - Sometimes fever or malaise palpable, fluctuating mass
Lymphadenopathy
- Sometimes
lymphadenopathy

- Aspiration
Differential - Type IV immune reaction Valciclovir 500mg TID for 5 days Check algorithm Nodules
- Cystic granuloma (early - Vascular compromise - Bacteriology
- Edematous granuloma (early
Diagnosis onset unusual)
onset unusual) (necrosis)

See Nodules Signs of No evidence of

systemic infection microorganisms
Section Yes (fever, chills, malaise) or No
- Swab for
for culture
culture critical localization (e.g.
Diagnostics - Antibiotics DD Cystic Granuloma, Future treatments:
- Antibiotics Drainage area of
- In severe cases, referral to a - Anti -viral therapy treat as LIRS Valciclovir 500 mg BID for 3 days
/ Therapy hospital
- In severe cases, referral to a angular vein)
as prophylaxis
hospital Check algorithm Nodules ,

- Admission to hospital Consider blood tests:

- Take care to create an - Take care to create an - Antibiotics IV BC, CRP
aseptic environment aseptic environment - Regular history of herpes:
Prophylaxis during treatments! during treatments! valciclovir 500 mg BID for 3
- Use only high quality - Use only high quality days as a prophylaxis
products products
No Penicillin Yes
allergy?
Figure 7
Amoxicillin / clavulanate Clindamycin 600mg TID
Infections (differential diagnosis) 625mg TID for 7 -10 days for 7 -10 days

Lack of Improvement Lack of improvement

- Change the class of antibiotics (e.g. clindamycin + quinolones)

- Blood tests: BC, CRP (course?)
- Consider imaging (extension?)
Erysipelas and cellulitis can be considered manifestations of the same condition and the terms are often used - Consider admission to hospital or consult ID specialist
- Bacteriology possible?
interchangeably. They are acute, painful, and potentially serious infections of the skin and subcutaneous tissues. The - DD: Type IV immune response, LIRS?

most common causative organisms are Streptococcus or Staphylococcus spp. Erysipelas is almost always caused by
β-hemolytic streptococci and consists of a superficial cutaneous process in the dermis, with prominent lymphatic
involvement. It has 3 distinguishing features: lesions are prominent, bright red, with clear demarcation between Figure 8
involved and uninvolved tissue. Streptococcal cellulitis is an acute spreading inflammation of large areas of skin and Infections (algorithm)
subcutaneous tissues. Clinical findings include local pain, tenderness, swelling, and erythema, whereas systemic
features include fever, chills, malaise, and lymphangitis, and/or bacteremia.39

Mild forms may be treated with oral antibiotics, while more serious cases require intravenous antibiotics and
hospitalization. Amoxicillin/clavulanate 625 mg TID or clindamycin 600mg TID for 7–10 days is recommended. In
unresolved cases, specialist infectious disease advice should be sought.

Abscess formation is rare but can occur any time from weeks to months following treatment. Abscesses should be
treated with antibiotics, incision, and drainage, with cultures being obtained and treatment tailored to sensitivity
reports.1,9,20 The most common organism is S. aureus.40 If the abscess emerges late (weeks to months postinjection)
and cultures are negative, the abscess may represent a cystic granuloma24 and should be treated as a late
inflammatory reaction (Fig. 5).

144 chapter 8 145

 Vascular Compromise Vascular-related events are major, immediate complications that result from intravascular injection into an artery,
causing an embolism that obstructs blood flow. This potentially leads to tissue anoxia, ischemia and possible
Vascular complications are rare following dermal fillers, but numbers are rising due to increases in dermal filler use. progression to necrosis (both anterograde and retrograde).9,41 Localized color changes should increase suspicion
The risk increases when bolus technique and smaller needles instead of cannulas are used.41 For this article, the of vascular compromise. An immediate onset blanching, followed by livedo reticularis (marbling) usually occurs
discussion is focused on peripheral ischemia with impending tissue necrosis and retinal ischemia (Fig. 9). within hours after injection due to lack of oxygen resulting in venous dilation. The blue-gray phase follows later due
to sustained lack of oxygen, and 1–2 days later the blister phase indicates the first signs of skin necrosis. Clinicians
should have detailed knowledge of facial anatomy since the rich vascular network of the face provides numerous
potential target sites. Recognition of a vascular event must be swift, followed by aggressive treatment to avoid serious,
Vascular Compromise (Differential Diagnosis) potentially irreversible complications, such as tissue necrosis and permanent vision loss.41

Treatment recommendations for peripheral ischemia are prompt administration of high-dose hyaluronidase41,42 and
Diagnosis Peripheral ischemia with impending necrosis Retinal ischemia warm compresses. Half-life time of hyaluronidase is short, so injections should be repeated hourly until capillary refill
improves.42 If blanching persists, lidocaine without epinephrine can be added to promote vasodilation. Low-dose
acetylsalicylic acid (ASA) may be given for 7 days; however, evidence for its benefit is low. Topical nitropaste is no
1. Blanching phase
- Immediate onset, duration < 1min, sometimes painful longer recommended, as studies in animal models have shown no benefit.43
2. Livedo reticularis phase (marbling)
- After a few minutes (seldom within a few hours), due to lack of oxygen
Clinical resulting in venous dilation, virtually pathognomonic
presentation 3. Blue -gray phase
- During Injection or immediately after injection: loss of vision, sometimes
concurrent eye pain Retinal ischemia is a rare but serious complication that occurs when the dermal filler inadvertently enters the ocular
- Tens of minutes to hours, due to sustained lack of oxygen . May appear
and time of - Over the course sometimes ophthalmoparesis
occurrence 4.
more rapidly in the vermillion.
Blister phase
circulation through retrograde arterial flow into the ophthalmic artery.44 Immediate blurring and potential visual
5.
- After 1 -2 days, as a first sign of skin necrosis
Demarcation and ulceration phase
blindness can result due to the injected material moving distally to the retina and blocking blood supply.9 As the
- After days to weeks, healing by secondary intention
ophthalmic artery communicates directly with the circle of Willis, intracerebral infarctions are possible and associated
symptoms like loss of consciousness or vertigo may be observed.45
- Vasoconstriction due to epinephrine containing local anesth. (blanching phase)
Differential
- Hematoma (blue -grey phase) - None
diagnosis - Herpes simplex / herpes zoster lesions (blister phase)
Treatment recommendations are primarily based on expert opinions and therefore have low level of evidence.
One drop of topical timolol 0.5% can be applied to the impaired eye to reduce intraocular pressure.46 The next
- Retrobulbar injection of hyaluronidase within 30 minutes
-
-
High dose hyaluronidase within a few minutes to hours
Warm compresses
- If retrobulbar injection cannot be performed by the injector: immediate referral intervention step is rapid clearance of retinal HA emboli. Carruthers et al.47,48 suggested retro- or parabulbar injections
to a (well -briefed) ophthalmologist
Therapy -
-
Aspirin
Further therapeutic options: Low -molecular-weight heparin (LMWH),
- Afterwards hospitalization: possibly PGE1 therapy, consider other medical of hyaluronidase; however, this procedure requires specialized training, so immediate referral to an ophthalmologist
therapies (HBOT, LMWH, pentoxyfillin)
pentoxyfillin, hyperbaric oxygen therapy (HBOT)
- MRI of the brain to rule out any cerebral ischemia may be needed. The speed of response is essential because of the extreme intolerance of the retina to hypoxia. There
are only a few reports on outcomes after retrobulbar hyaluronidase injections; Chesnut49 reported on one case of
-
-
Use blunt cannulas (25G) in high -risk areas
Small boluses (max. 0.05ml / bolus) in high -risk areas
visual loss restoration, but Zhu et al.50 were unable to clear retinal artery occlusion in 4 patients treated with high
Prophylaxis -
-
Slow injection
Aspiration (needle)
doses of retrobulbar hyaluronidase injected after 4 hours or longer. Fast vascular reperfusion has been demonstrated
- Consider manual compression of the angular artery during injection
- Risk factors: previous surgery, scars (including acne scars!), small -gauge needles / cannulas in animal models using both hyaluronidase and urokinase, and this may become a standard treatment option in
the future.51 In this animal study, the retinal embolus had to be removed within 45 minutes to prevent permanent
Figure 9 blindness but more research is needed to provide an estimate for the time limits of the human eye.
Vascular compromise (differential diagnosis)
After hyaluronidase treatment, the patient should be hospitalized, evaluated for retrobulbar hematoma, and a brain
magnetic resonance imaging obtained to rule out any cerebral ischemia. Further therapeutic options for retinal or
severe peripheral ischemia include prostaglandin E1 (PGE1) IV, pentoxifylline, low molecular weight heparins (LMWH)
and hyperbaric oxygen treatment and for peripheral ischemia, injection of platelet rich plasma. However, evidence
levels for all these treatments are low (Fig. 10).

146 chapter 8 147

 conclusions
Vascular Compromise (Algorithm) HA fillers are safe and effective for facial rejuvenation and, although adverse effects associated with their use
are uncommon, they do occur. Currently, there is a lack of standardized guidance on how to treat HA-related
complications that combine expert opinion with evidence from clinical trials. In this article, the authors have provided
Peripheral ischemia with impending necrosis Retinal ischemia practical recommendations for concise treatment algorithms based on clinical presentation of the complications rather
than the final diagnosis, using published expert opinions together with the authors’ experience. The focus is on the
common categories of complication associated with HA filler treatment: skin discoloration, edema, nodules, infection,
Symptoms Symptoms
1. Blanching 1. Loss of vision and vascular compromise. These guidelines are not intended to be complete or exhaustive but may prove informative
2. Livedo reticularis 2. Eye pain
for aesthetic clinicians as how best to recognize potential complications and provide clear guidance on optimum
treatment pathways.

Acute treatment Acute treatment

- Hyaluronidase - Retro- or parabulbar injection of 450 U hyaluronidase
- Start immediately - If cannot be performed by the injector: immediate referral to
- Up to 450 U for each square - inch of affected tissue a well -briefed ophthalmologist
- At the injection site and in the ischemic region - Transportation: accompanied by taxi or ambulance
- Repeat every hour until capillary refill improves - Timeframe: 30 (up to 40) minutes!
- Warm compresses
- ASA 500mg orally, then 75 -100mg OD for 7 days
Take note: Always give along enough quantity of
hyaluronidase. Do not refer to ER (time loss).

Continuous follow -up

(first next day)

Favorable course Poor course

- Pink coloration (reactive - Blue-grey discoloration After retrobulbar
hyperemia) - Blisters injection
- Ulceration

- In the first follow-up, consider injecting additional

Follow-up after 7 days and 4 - Hospitalization and treatment with prostaglandin E1
hyaluronidase
weeks (PGE1) IV
- Further therapeutic options:
- Pentoxyfillin 400mg TID (Beware: BP - MRI of the brain to rule out any cerebral ischemia
drop with NO) - Further therapeutic options:
- LMWH (e.g. enoxaparine 1.5mg/kg/day) - Pentoxyfillin 400mg TID
- HBOT - LMWH (e.g. enoxaparine 1.5mg/kg/day)
- Proper wound care - HBOT
- Consider plastic surgery consultation

Figure 10
Vascular Compromise (algorithm)

148 chapter 8 149

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Cosmetic surgery national data bank statistics. Available confirmed by microanalysis. Contact Dermatitis. 30. Orentreich DS. Liquid injectable silicone: techniques for 2006;20: 1130–1144.
at [email protected]. Accessed May 2018. 1998;39:144. soft tis- sue augmentation. Clin Plast Surg. 2000;27:595– 45. Lazzeri D, Agostini T, Figus M, et al. Blindness following
4. Philipp-Dormston WG, Bergfeld D, Sommer BM, et al. 18. Lachapelle JM, Tennstedt D. An anatomo-clinical study 612. cosmet- ic injections of the face. Plast Reconstr Surg.
Consensus statement on prevention and management of delayed skin allergic reactions to nickel following 31. Achauer BM. A serious complication following medical- 2012;129:995–1012.
of adverse effects following rejuvenation procedures intradermal injections of lidocaïne with a Dermo-jet. grade silicone injection of the face. Plast Reconstr Surg. 46. Loh KT, Chua JJ, Lee HM, et al. Prevention and
with hyaluronic acid-based fillers. J Eur Acad Dermatol Contact Dermatitis. 1982;8:193–199. 1983;71: 251–254. management of vision loss relating to facial filler
Venereol. 2017;31:1088–1095. 19. Bitterman-Deutsch O, Kogan L, Nasser F. Delayed 32. Duffy DM. The silicone conundrum: a battle of injections. Singapore Med J. 2016;57:438–443.
5. King M. The management of bruising following immune mediated adverse effects to hyaluronic acid anecdotes. Dermatol Surg. 2002;28:590–594. 47. Carruthers J, Fagien S, Dolman P. Retro or PeriBulbar
nonsurgical cosmetic treatment. J Clin Aesthet Dermatol. fillers: report of five cases and review of the literature. 33. Wolters M, Lampe H. Nicht—operative Faltenbehandlung injection techniques to reverse visual loss after filler
2017;10:E1–E4. Dermatol Reports. 2015;7:5851. im Gesicht. Plast Chir. 2003;2:69. injections. Dermatol Surg. 2015;41:S354–S357.
6. Shah NS, Lazarus MC, Bugdodel R, et al. The effects of 20. Kim JH, Ahn DK, Jeong HS, et al. Treatment algorithm 34. ischer J, Metzler G, Schaller M. Cosmetic permanent fillers 48. Carruthers JD, Fagien S, Rohrich RJ, et al. Blindness
topical vitamin K on bruising after laser treatment. J Am of complications after filler injection: based on wound for soft tissue augmentation: a new contraindication for caused by cosmetic filler injection: a review of cause and
Acad Dermatol. 2002;47:241–244. healing process. J Korean Med Sci. 2014;29:S176–S182. interferon therapies. Arch Dermatol. 2007;143:507–510. therapy. Plast Reconstr Surg. 2014;134:1197–1201.
7. Cohen JL, Bhatia AC. The role of topical vitamin K oxide 21. Jones D, Tezel A, Borrell M. In vitro resistance to 35. López-Pestaña A, Tuneu A, Lobo C, et al. Granulomas 49. Chesnut C. Restoration of visual loss with retrobulbar
gel in the resolution of postprocedural purpura. J Drugs degradation of hyaluronic acid dermal fillers by ovine sarcoideos en material de relleno facial inducidos por hyaluronidase injection after hyaluronic acid filler.
Dermatol. 2009;8:1020–1024. testicular hyaluronidase. Dermatol Surg. 2010;36:804– interferon y ribavirina en pacientes con hepatitis C. Actas Dermatol Surg. 2018 Mar;44(3):435–437.
8. Toole BP. Hyaluronan: from extracellular glue to 809 Dermosifiliogr. 2011;102:746–747. 50. Zhu GZ, Sun ZS, Liao WX, et al. Efficacy of retrobulbar
pericellular cue. Nat Rev Cancer. 2004;4:528–539. 22. Rao V, Chi S, Woodward J. Reversing facial fillers: 36. Saththianathan M, Johani K, Taylor A, et al. The role of hyaluronidase injection for vision loss resulting from
9. Funt D, Pavicic T. Dermal fillers in aesthetics: an overview interactions between hyaluronidase and commercially bacterial biofilm in adverse soft-tissue filler reactions: a hyaluronic acid filler embolization. Aesthet Surg J. 2017.
of adverse events and treatment approaches. Clin Cosmet available hyaluronic-acid based fillers. J Drugs Dermatol. combined labora- tory and clinical study. Plast Reconstr doi: 10.1093/asj/sjw216 [Epub ahead of print].
Investig Dermatol. 2013;6:295–316. 2014;13:1053–1056. Surg. 2017;139:613–621. 51. Chiang C, Zhou S, Chen C, et al. Intravenous
10. Taylor SC, Burgess CM, Callender VD. Safety of nonanimal 23. Kim DW, Yoon ES, Ji YH, et al. Vascular complications 37. Alhede M, Er Ö, Eickhardt S, et al. Bacterial biofilm hyaluronidase with urokinase as treatment for rabbit
stabilized hyaluronic acid dermal fillers in patients of hyaluronic acid fillers and the role of hyaluronidase formation and treatment in soft tissue fillers. Pathog Dis. retinal artery hyaluronic acid embolism. Plast Reconstr
with skin of color: a randomized, evaluator-blinded in management. J Plast Reconstr Aesthet Surg. 2014;70:339–346. Surg. 2016;138:1221–1229.
comparative trial. Dermatol Surg. 2009;35:1653–1660. 2011;64:1590–1595. 38. Schelke LW, Decates TS, van der Lugt CIM, et
11. Heath CR, Taylor SC. Fillers in the skin of color 24. Lemperle G, Gauthier-Hazan N, Wolters M, et al. Foreign al. Intralesional laser treatment for dermal filler
population. J Drugs Dermatol. 2011;10:494–498. body granulomas after all injectable dermal fillers: part 1. complications. Plast Reconstr Surg. 2018;141:1361–1369.
Possible causes. Plast Reconstr Surg. 2009;123:1842–1863.

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 09
Managing Intravascular
Complications Following
Treatment with Calcium
Hydroxylapatite:
An Expert Consensus
First Author. Impact Factor 1.903, SJR 0.807

J Cosmet Dermatol. 2020 Mar 17. doi: 10.1111/jocd.13353

Jani van Loghem,1 David Funt,2 Tatjana Pavicic,3 Kate Goldie,4 Yana Yutskovskaya,5 Sabrina Fabi,6
Pieter Siebenga,1 Job Thuis,1 Joseph Hkeik,7 Jonathan Kadouch,8 Welf Prager,9 Nabila Azib,10
Gabriela Casabona,11 Steve Dayan,12 Shino Bay Aguilera,13 Philippe Snozzi,14 Peerooz Saeed1,15

1. UMA Institute. Aesthetic Medicine Centre, Amsterdam, The Netherlands. Falckstraat 51, Amsterdam, Netherlands
2. Mount Sinai School of Medicine, New York, NY, Garden City, NY, Woodmere, NY, USA.
3. Private Practice for Dermatology and Aesthetics, Munich, Germany.
4. European Medical Aesthetics Ltd, London, United Kingdom.
5. Dermatovenerology and Cosmetology Department, Pacific State Medical University of Health, Moscow, Russia.
6. Department of Dermatology, University of California, San Diego, CA, USA.
7. All Saints Clinic, Double Bay, Sydney, Australia
8. ReSculpt Clinic, Practice for Aesthetic Dermatology, Amsterdam, The Netherlands.
9. Prager & Partner Dermatologische Praxis, Hamburg, Germany.
10. Chirurgie Plastique, Réparatrice et Esthétique, Rabat, Morocco.
11. Scientific Department, Ocean Clinic, Marbella, Spain.
12. Division of Facial Plastic and Reconstructive Surgery, Department of Otolaryngology, University of Illinois at Chicago, Chicago, IL, USA.
13. Nova Southeastern University College of Osteopathic Medicine, Department of Dermatology, Fort Lauderdale, FL, USA.
14. Smoothline Clinic, Zürich, Switzerland
15. Departments of Ophthalmology and Endocrinology, Orbital Center, Academic Medical Center, University of Amsterdam,
Amsterdam, The Netherlands.

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 abstract
Background Results
Inadvertent intra-arterial injection of dermal fillers including For prevention of intra-arterial CaHA injection, consensus
calcium hydroxylapatite (CaHA) can result in serious adverse members outlined the importance of a thorough knowledge
events including soft-tissue necrosis, permanent scarring, visual of facial vascular anatomy and patient history, as well as
impairment, and blindness. When intra-arterial injection occurs highlighting potential risk zones and optimal injection
immediate action is required for optimal outcomes, but the techniques. Individual sections document how to recognize
infrequency of this event means that many physicians may never the symptoms of vascular occlusion leading to vision loss
have experienced this scenario. The aim of this document is to and tissue necrosis as well as detailed treatment protocols
provide evidence-based and expert opinion recommendations for the management of these events. For impending tissue
for the recognition and management of vascular compromise necrosis, recommendations are provided for early and delayed
following inadvertent injection of CaHA. presentations with treatment protocols for acute and follow-up
treatment. A separate section details the treatment options for
Methods open and closed wounds.
An international group of experts with experience in injection
of CaHA and management of vascular complications was Conclusions
convened to develop a consensus on the optimal management All aesthetic physicians should be prepared for the eventuality
of vascular compromise following intra-arterial CaHA of intra-arterial injection of a dermal filler, despite its rarity.
injection. The consensus members were asked to provide These consensus recommendations combine advice from
preventative advice for the avoidance of intravascular injection aesthetic experts with the latest reports from the published
and to produce a treatment protocol for acute and delayed literature to provide an up-to-date office-based protocol for
presentation. To ensure all relevant treatment options were the prevention and treatment of complications arising from
included, the recommendations were supplemented with intra-arterial CaHA injection.
a PubMed search of the literature.

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 introduction consensus objectives and methodology
In the past two decades, the popularity of injectable dermal fillers to correct aging-related soft tissue volume loss and CaHA is one of the most versatile dermal fillers with a long history of aesthetic use.16,17 It is widely used for indications
contour defects has increased dramatically. Along with neurotoxin injections, these products represent the mainstay ranging from volumizing and contouring, and more recently in hyperdiluted form for skin rejuvenation.18–21 The risk of
of most medical aesthetic practices.1,2 Among the soft tissue fillers, hyaluronic acid (HA) products are most commonly severe adverse events as a result of inadvertent intra-arterial injection is very rare, but all injectors using this product
used, followed by calcium hydroxylapatite (CaHA, Radiesse®; Merz North America, Inc., Raleigh, NC, USA), and should have an in-depth understanding of how this may occur, how to avoid it, how to recognize it, how to limit
poly-L-lactic acid (Sculptra, Galderma®, Fort Worth, TX, USA).1,2 Although these products are considered to be safe vascular compromise should it occur, and how to treat the resulting sequelae. The current recommendations have
(within their approved indications and when injected by qualified professionals), the potential risk for severe adverse addressed this need by bringing together a group of 17 international aesthetic experts with experience in injection of
events remains regardless of the filler used.3,4 CaHA and the management of CaHA-related complications. The format was slightly different from most consensus
papers in that there were no face-to-face meetings. The process was initiated in November 2018 when consensus
In a cross-sectional review, the complication profile associated with injectable fillers was evaluated by searching the members were asked to produce a treatment protocol for immediate and late measures to be taken after intra-arterial
databases of the US Food and Drug Administration (FDA) and Manufacturer And User facility Device Experience injection of CaHA, and to give preventative advice for the avoidance of intravascular injection. A comprehensive
(MAUDE). From 2014 to 2016 a total of 1,748 adverse events were reported.5 Intra-arterial injections without sequelae literature search was also conducted using the PubMed database and the following search terms: calcium
and those resulting in necrosis or blindness were considered severe complications and were reported in 220, 121, and hydroxylapatite, Radiesse, vascular compromise, vascular occlusion, vascular necrosis, visual impairment, vision loss
8 cases, respectively, the latter most commonly after dorsal nasal injections. and blindness; articles were limited to those published in English. A first draft was prepared based on the information
collected and a draft circulated to the group for their comments and precision. Areas of disagreement were identified
Vascular compromise and occlusion may occur with any dermal filler following inadvertent intra-arterial injection, and a questionnaire circulated allowing members to vote on contentious areas.
and it is generally the volume of product injected rather than filler type that has the greatest impact: the larger the
bolus and the larger the branch of the artery that is embolized, the larger the area of necrosis. All injectors must be The current document represents the culmination of this process. In light of new scientific knowledge, treatments
aware of the type of adverse events that can occur and how to treat them. A comprehensive understanding of facial for filler-induced vascular compromise are constantly improving. The aim of this paper was to collate all successful
anatomy and dermal filler characteristics is essential. Given the rarity of vascular compromise, physicians might not treatment options into one document and based on this information to provide an up-to-date protocol for treatment
have any experience in the recognition nor management of these complications. based on expert consensus and the latest treatment techniques. The specific recommendations presented in this
article represent the panel’s expert opinion based on their collective clinical experience and published data regarding
For hyaluronic acid based fillers, a number of aesthetic physicians have proposed protocols for the management of vascular compromise with CaHA in the cosmetic setting.
vascular compromise using hyaluronidase,6–9 and several consensus documents have been published.10–13 Treatment
protocols have been proposed for vascular compromise following CaHA injections,6,14,15 but to date no specific
consensus guidelines exist. Calcium hydroxylapatite aesthetic indications

Approved aesthetic indications of CaHA are for facial soft tissue augmentation including the correction of moderate-
to-severe facial wrinkles and folds, such as nasolabial folds and to correct volume loss in the dorsum of the hands.22–24
With the recognition that facial aging occurs at all anatomical layers, expanded, albeit off-label indications, for CaHA
have been developed that make use of its rheological properties, and in addition to soft-tissue lifting it is now also
widely used to restore contours affected by age-associated bone resorption, replenish fat loss, and most recently
in diluted form to improve skin laxity. The product’s instructions for use warn that special care should be taken to
avoid injection into the vasculature, particularly in high-risk areas that are dependent on blood supply from a single
arterial branch such as the glabella, nose and nasolabial folds.25 However, all facial arteries are potentially vulnerable
to intravascular injection and once the product has been injected intravascularly, the product travels through the
vasculature and may result in local or distal necrosis. Intravascular occlusion of facial arteries is solely due to injector-
dependent technical errors and can be avoided with a comprehensive knowledge of vascular anatomy and proper
injection technique.

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 results
Prevention Lowest risk
Area Indication High risk Average risk Low risk
anatomical level
Anatomy and patient history Medial cheek [1] IOA (d) FA (sf) AA Sub-SMAS,
(sf) subcutaneous
A thorough discussion of the facial (three-dimensional arterial) anatomy relevant to dermal filler injections is beyond
Nasolabial folds [1] SLA (d) FA (sf) AA Supra-periosteal
the scope of this review, but the reader is referred to a series of publications based on anatomical dissections designed
(sf)
to promote safe patient outcomes after nonsurgical aesthetic treatment, a number of which were co-authored by
members of this consensus group and are relevant to facial areas typically treated with CaHA injections.26–34 Mandibular area Mandibular angle [1] ECA (d) FA (d) Subcutaneous

A complete patient medical history should be obtained at the initial consultation including details of all previous
Pogonium [1] ILA (d) Supra-periosteal,
aesthetic treatments and surgery as these can alter the patient’s baseline anatomy. Physicians should also be aware subcutaneous
that there are large variations between individuals in the branching patterns of many arteries.35,36 Patients who have
undergone previous cosmetic procedures such as rhinoplasty may have unpredictable repositioning of blood vessels Mentum [1] SMA(d), ILA (d) Supra-periosteal,
and a more tenuous blood supply in the operated area, which may increase the risk of ischemia, necrosis, and subcutaneous

vascular embolism following the filler injection.37 Previous tissue scars may also fix arteries in place, making them
Marionette lines [1] SMA(d), ILA (d), Subcutaneous
easier to penetrate with small sharp needles or even cannulae. FA (d)

Prejowl sulcus [1] SMA(d), ILA (d), Supra-periosteal,

FA (d) subcutaneous

Table 1
Risk zones for CaHA injection Commonness of indication: [1] regular CaHA indication, [2]: not a common CaHA indication; [3]:
contraindication for CaHA. Usual depth of the artery: (sf): superficial: subcutaneous, (d): Deep: underneath
Lowest risk the superficial musculo-aponeurotic system (SMAS), (if): interfascial.
Area Indication High risk Average risk Low risk
anatomical level Arteries and their branches. SOA: supra orbital artery, STRA: supratrochlear artery. STA: superficial
Frontal area Frontal concavity [2] SOA (d) and STRA SOA (sf), STRA (sf) Supra-periosteal temporal artery, IOA: infraorbital artery, ZFA: zygomaticofacial artery, ADTA: anterior deep temporal artery;
(d) within 2cm of the STA (sf)* >2cm abo- PDTA: posterior deep temporal artery, AA: angular artery, LNA: lateral nasal artery, DNA: dorsal nasal
supraorbital rim ve the supraorbital
rim artery, CA: columellar artery, TFA: transverse facial artery, SLA: superior labial artery, ILA: inferior labial
artery; ECA: external carotid artery, SMA: submental artery
Periorbital area Brows [2] SOA (d) STA (frontal Supra-periosteal,
branch sf) subcutaneous *deep, subgaleal should be the safest plane of injection, but considering other risk factors like multi-level
trajectory of the STRA and SOA in the 2 cm superior to the supraorbital rim not regarded as lower risk.
Glabella [3] STRA (d) Contra-indicated

Tear troughs [2] IOA (d), AA (sf) Supra-periosteal

Risk zones
Palpebromalar ZFA (d) Supra-periosteal
groove [2] Areas of the face that have the highest risk of vascular occlusion are those with extensive anastomoses between
vascular territories (Figure 1), because of the risk of occluding adjoining smaller diameter arteries, e.g. central retinal
Temporal area Temporal hollows [1] STA (sf), ADTA (d), STA (if) Interfascial
PDTA (d) artery,8 and those with a poor source of collateral circulation,5,38,39 such as the end arteries of the nasal tip and ala
(Table 1). Injections to the nasal area have been reported as the main cause of tissue necrosis and the second cause of
Nose Nasal tip [2] LNA (sf), CA (sf) Not recommended visual loss.40,41

Nasal dorsum [2] DNA (sf) Supra-periosteal

Ala [2] LNA (sf) Not recommended

Columella [2] CA (sf) Sub-SMAS

Cheeks Lateral cheek [1] ZFA (d), TFA Supra-periosteal,

(d) subcutaneous

Continued on next page

158 chapter 9 159

 The glabella is the most common filler injection site triggering blindness as small vessels branching from the
supratrochlear artery provide the blood supply to the glabellar region and connect to the central retinal artery via the
ophthalmic artery. In the area of the nasolabial fold and nasal dorsum there are anastomoses between the facial,
angular, and lateral nasal arteries (external carotid circulation) with the dorsal nasal artery, which is a branch of the
ophthalmic artery (internal carotid circulation) (Figure 2).32 Injection into the nasolabial fold or nasal dorsum may
therefore accidentally deliver product intra-arterially, and if plunger pressure is greater than arterial pressure, product
can move proximally into the central retinal artery. In the temporal region, anastomoses can exist between the frontal
branch of the superficial temporal artery and the supraorbital, supratrochlear, and zygomatico-temporal arteries
(Figure 2), thus allowing a filler to be propelled retrograde into the central retinal artery.32

Figure 2
Possible pathways of central retinal artery embolization.
ICA: internal carotid artery, OA: ophthalmic artery, SOA: supraorbital artery, STRA: supratrochlear artery,
CRA: central retinal artery, ENA: external nasal artery, DNA: dorsal nasal artery AA: angular artery.
Figure 1 Red arrows: direction of blood flow, white arrows: direction of filler displacement.
Illustration of the main facial arteries and their anastomoses. Illustration: © Jani van Loghem.
FA: facial artery, AA: angular artery , LNA: lateral nasal artery, DNA: dorsal nasal artery, STA: superficial
temporal artery, (fb): frontal branch (pb): parietal branch, MTA: middle temporal artery; ADTA: anterior deep
temporal artery, PDTA: posterior deep temporal artery, SOA: supraorbital artery, STRA: supratrochlear
artery, ZFA: zygomatico-facial artery, IOA: infraorbital artery, TFA: transverse facial artery, CA: columellar To minimize risk, injections should always be performed slowly, with low volume and attention paid to the pain
artery, PA: philtral artery, SLA: superior labial artery, ILA: inferior labial artery, SMA: submental artery, ECA: feedback received from the patient. In addition, the authors advise not to exceed 0.025 ml per injection volume in the
external carotid artery. Illustration: © Jani van Loghem. area close to the supratrochlear notch.42,43

160 chapter 9 161

 Injection technique Vascular occlusion leading to vision loss

For a detailed description of the anatomical planes that offer the least arterial risk in injection danger zones the reader Recognizing the symptoms
is referred to the papers of Criollo-Lamilla et al. and Cotofana & Lachman.33,44 In order to avoid the supratrochlear and
supraorbital vasculature with cosmetic filler injections, Carruthers et al. recommend inserting the needle or cannula A disruption of the blood supply to the retina can occur after dermal filler injection in almost any area of the face and
into the subgaleal space superior to its transition from preperiosteal to subcutaneous level.45 Van Loghem et al.46 results in a sudden onset of impairment/loss of vision accompanied by severe pain (ocular, facial, and/or headache).
suggest the use of a cannula when treating the frontal area and have published techniques for injections in Cerebral infarction can accompany retinal artery occlusion, and therefore signs and symptoms such as aphasia or
this zone.17,43 even contralateral hemiparesis might also be present.54

CaHA should be injected slowly, with a low injection force and with the smallest amount of product necessary. For
deep injections the periosteum remains the preferred location, but with caution as there is no guarantee that Management of impending vision loss (Figure 3)
injections will be extravascular. Large boluses should be avoided and injection volumes limited to 0.1 ml, and 0.025
ml in the periorbital area. When using a needle in a danger zone, material should be deposited at the preperiosteal Once the retinal artery has been occluded, only a short window of opportunity of about 60 minutes exists to
level with the needle in contact with the periosteum and at a slightly oblique angle with the bevel down. Although reestablish retinal perfusion before blindness is irreversible.55 Only one case report has described a partial vision
flow of product can be reduced by using the smallest gauge needle size possible, small needle calibre increases recovery after CaHA-induced retinal artery occlusion, which involved application of topical and systemic intraocular
plunger pressure and the likelihood of clogging, which may cause the injector to increase the pressure on the plunger pressure lowering agents, isovolemic hemodilution, ocular massage and aspirin anticoagulation, as well as carbon
and thus the risk of serious adverse events should the needle be intravascular. Large gauge needles increase the risk of dioxide inhalation, oral corticosteroids and hyperbaric oxygen therapy.56 The patient must be transferred immediately
bruising, but might decrease the risk of intravascular injections. If unexpected resistance is detected, blanching to the nearest ophthalmologist with as much information as possible regarding the product, injection site(s), and the
observed, or the patient indicates pain, the injection must be stopped immediately. volume of injection.

Aspiration is often advocated as a method for avoiding intravascular injection, the appearance of blood in the syringe The goal is rapid reduction of intraocular pressure to allow the emboli to dislodge downstream and improve retinal
indicating the needle has entered an artery. However, it is important to note that the absence of blood in the needle perfusion. Acute management involves eyeball massage to promote a lowering of the intraocular pressure and to
hub on aspiration is no guarantee of avoidance. This has been demonstrated by the results of a recent in vitro study advance the product through the retinal vessels. The technique involves small rapid changes of intraocular pressure
where non-diluted CaHA (with and without integrated lidocaine) showed negative test results with anticoagulated over a period of 1 to 3 hours, until all retinal emboli have been cleared from the vessel. Ocular massage is performed
blood with a variety of needles (23-33G), even after 10 seconds of aspiration with 0.5 ml negative pressure.47 CaHA with the patient in a supine position, looking downward with their eyes closed.32 Gentle pressure is applied to the
with standard dilution (16.7% lidocaine) showed positive test results within 1 second using needles of 27G or thicker sclera of the anesthetized eye with a finger, indenting the globe by a few millimeters and then releasing at a frequency
with a 0.8 ml CaHA syringe and aspiration times of 3 seconds (27G, 13mm and 25G, 13mm) and 7 seconds (23G, of 2 to 3 times a second.32,57 The prolonged, rapid small changes in intraocular pressure have been found to be more
19mm) with the 1.5 ml syringe. Some research has suggested that a slow-pull retraction and up to 5 sec waiting time conducive to dislodging emboli than a brief high-pressure aggressive massage of the eye. The procedure should be
may improve the reliability of the aspiration test.48 continued until the patient reaches the treating ophthalmologist in the hospital.

Aspiration test results are influenced by needle diameter, needle length, syringe, and rheological properties of the An additional acute measure is to encourage the patient to “re-breathe” exhaled air in a paper bag to increase carbon
filler material, making general remarks on reliability of aspiration difficult, other than to conclude that aspiration is dioxide levels in the blood, which will cause the retinal arteries to vasodilate and could help dislodge the
unreliable.47,49 When using a sharp needle near a foramina, enter obliquely and if possible pinch the tissue away from blockage.32,58 The patient should be given aspirin 500 mg (Europe) or 625 mg (US) to avoid blood clotting upstream to
the bone. the CaHA embolus.

The use of blunt cannulae decreases the risk of intravascular injection, but all cannulae (except the 10G size which is Sodium thiosulphate (STS) 25 g IV over 10-30 minutes (standard protocol for cyanide poisoning) could theoretically
not generally used in facial aesthetic medicine) can enter arteries and are therefore not 100% safe.34,50 Cannulae 25G dissolve parts of the microspheres blocking the retinal vessels. Without any clinical evidence that intravenous STS can
or larger require greater force to enter a vessel than a needle, while smaller cannulae 27G and 30 G are similar to dissolve intravascular CaHA emboli, there was discussion among the consensus group on advising this experimental
needles. Parallel injections to the direction of the local arteries should be avoided as well as using force through option. However, as blindness is a devastating complication and since intravenous STS is associated with minimal
resistances that could contain arteries. Areas where arteries have limited space to be pushed aside pose a particular adverse events, the administration could be justified. Due to the very rare occurrence of metabolic acidosis after STS
risk, including post-surgical areas and neurovascular bundles. infusion, the infusion could be given when reaching the hospital.

Other options to decrease the risk of vascular compromise include injecting in a retrograde fashion with a constantly Administration of a beta-adrenergic antagonist in the form of eye drops (e.g. Timolol 0.5% with brinzolamide 1%) will
moving needle so as not to deliver a large deposit in one location. The use of adrenaline (epinephrine)-containing also help to reduce intraocular pressure; acetazolamide may be of benefit if administered intravenously and
local anesthesia promotes arterial constriction, reducing the size of vessels and therefore the risk of filler entry. intravenous dexamethasone may be administered to decrease inflammation. These intravenous medications as well as
However, products containing adrenaline may mask blanching produced by occlusion.51 Tumescent injection, also hyperbaric oxygen therapy may be administered in the hospital as they are not readily available in private clinics.
known as saline hydrodissection, has been used successfully when performing CaHA injections of the forehead.52,53
The tumescent solution for tissue hydrodissection creates a pocket of space for filler placement, and allows the Oral pentoxifylline at a dose of three 400 mg tablets daily has been shown to improve retinal flow more than placebo
physician to reduce bleeding and prevent vessel compromise. in patients with sudden loss of vision as a result of retinal vein thrombosis, although no improvement in vision was
demonstrated (Figure 3).59

162 chapter 9 163

 CaHA Vascular Complications (Overview) CaHA Vascular Complications (Algorithm)

Retinal ischemia Peripheral ischemia with impending necrosis

Diagnosis Retinal Ischemia Peripheral Ischemia with threatening necrosis

Symptoms Symptoms
1. Sight loss 1. Blanching
2. Eye pain 2. Livedo reticularis
1. Blanching phase 3. Blue-grey
- Immediate, onset <1min, may be painful. 3. Vertigo
discoloration
2. Livedo reticularis phase (marbling)
- After a few minutes (seldom within a few hours),due to lack of oxygen resulting
- Simultaneous occurrence of loss of vision and eye pain.
in venous dilation, virtually pathognomonic.
Symptoms - Mostly simultaneously ophthalmoparesis, ptosis, vertigo, fainting.
3. Blue-grey phase
- Peripheral ischemic symptoms may be present (blanching). - After a few quarters of hours to two days, alternating signs of sustained lack of oxygen.
4. Pimple phase Acute treatment Acute treatment up to 6 hours after onset of symptoms
- After 1-4 days, signs of skin necrosis. - Arrange transportation to ophthalmologist: by taxi or ambulance - Hyaluronidase in lidocaine injection in affected area
5. Demarcation and ulceration phase - Timeframe: 60 minutes for recirculation before permanent visual loss - within a few minutes to hours
- After days to weeks, secondary wound healing. - Eyeball massage (indent globe 1-3mm, 2-3x /s for 3 hours) - 600U per 0.1 ml intravascular CaHA, every 2 hours
- Rebreathe CO2 (in a bag) - Warm compresses and massage for 5 minutes every 1-2 hours
- Aspirin 500 mg (Europe) – 625 mg (US) - Aspirin 500 mg (Europe) – 625 mg (US) orally daily for 3-5 days
- Timolol 0.5% eyedrops / Brinzolamide 1% eyedrops - 20 mg Tadalafil orally daily for 3-5 days
- Prednisone oral tapering course over 7 days: 50-50-30-30-10-10-5 mg
- Consider LMWH injection daily for 3-5 days
- Vasoconstriction due to adrenalin in anaesthesia (blanching phase).
Differential
- Panic attack, optic neuritis, migraine, stroke or transient ischemic attack. - Hematoma (blue-grey phase).
diagnosis - Herpes simplex lesions (pustula phase).
During follow-up

Transportation Poor circulation

Good circulation
- Double check vision loss. to hospital: after 6 hours
Pink coloration
- Immediate consultation and transport to ophthalmologist. continuing - Dark discoloration,
- Hyaluronidase within a few minutes to hours. (reactive hyperaemia)
- Ocular massage: 2-3x/sec indenting the sclera a few mm until hospital. eyeball massage - Slow capillary refill
- Warm compresses.
Therapy - Aspirin orally, Timolol 0.5% brinzolamide 1% eyedrops. - Aspirin, tadalafil, prednisolone, pentoxyfilline.
- Rebreathe in paper bag to increase CO2 (will dilate retinal vessels). - Hyperbaric oxygen therapy, PRP, LED, RF, Laser.
- Hospitalization and possibly i.v. therapy of PGE1, dexamethasone,
oral pentoxyfilline and hyperbaric oxygen therapy.

In hospital (still acute treatment) Follow-up after 7 days and 4 - Inject additional hyaluronidase
- I.v. dexamethasone weeks - Continue aspirin, tadalafil and prednisone daily
- Further therapeutic options (low level of evidence): - Further therapeutic options (low level of evidence):
- Prostaglandin E1 (PGE1) i.v. - Pentoxifylline 400 mg 1-1-1 orally
- Use atraumatic cannulas (25G or thicker) in high-risk areas. - Pentoxyfilline 1-1-1 400mg orally - Hyperbaric oxygen therapy
- Gentle tissue handling. - Acetazolamide 250-375 mg/day i.v. - PRP treatment
How to - Slow injection rate. - LMWH - Red LED light
- Small volumes: max. 0.1 ml / bolus. Periorbital close to the branches of the ophthalmic artery: max. 0.025 ml / bolus. - Hyperbaric oxygen therapy - Bipolar RF
prevent - Sharp needle: periosteal injections: bevel down, angled approach, pull tissue away from bone, avoid foramina. - Topical and systemic antibiotics
- Superficial injections: intradermal. Subdermal: retrograde small amounts < 0.1 ml (avoid bolus technique). - Systemic antivirals if history of H. simplex
- Avoid tissue where arteries may have little room to be pushed aside like scars, neurovascular bundles, foraminae. - Proper wound care: debridement and moist dressing
- Periorbital area/nose: press on supratrochlear /dorsal nasal arteries with non-dominant fingers to temporarily block blood flow. with open wounds
- Avoid small-gauge needles and cannulas. - Laser or micro-needling therapy after wound closure

Figure 3 Figure 3
A B

Figure 3
Overview (A) and treatment algorithm (B) of CaHA induced retinal ischemia with acute vision loss and
peripheral ischemia with impending necrosis. CO2: carbon dioxide. LMWH: low molecular weight heparin
anticoagulants, I.v.: intravenous, CaHA: calcium hydroxylapatite, U: units, PRP: platelet rich plasma, RF:
radio frequency.

164 chapter 9 165

 Vascular occlusion leading to peripheral ischemia and tissue necrosis A B C D E

Recognizing the symptoms

The incidence of impending necrosis following dermal filler treatment has been estimated as 1 in 100,000 cases
(0.001%),51 although consensus members felt this estimate was too optimistic and in their experience was at least
1:10,000, particularly among less experienced injectors and when long, sharp needles are routinely used. The usual
initial presentation of vascular compromise and occlusion is a disproportionate pain to what can be expected.
However, the excessive pain may be masked due to the anesthetics mixed in certain fillers to an extent that in most
cases, no significant pain is perceived at all. Pallor and blanching usually present themselves immediately, and follow F G H I J
the same pattern as the restricted blood supply pathway. A livedo reticularis reaction (mottled discoloration) may
follow in 1-10 min and can last for several hours. Progressive symptoms include hemorrhagic changes and sometimes
reduced sensitivity (24-48 hrs), blisters and pustules (4-6 days) and necrosis (5-10 days) (Figure 4, Figure 5). Finally,
secondary infection may occur.

In some cases patients may not complain of symptoms or show signs of ischemia during the filler injection or even on
the day of the procedure.15,60 A possible explanation for this delayed onset is that the filler is trapped at a bifurcation or
branch point, and becomes dislodged at a later timepoint to cause an occlusion.61
Figure 5
(Courtesy Y. Yutskovskaya). A female patient aged 34 years old with no skin pathologies or history of allergy
was treated for correction of the nasal bridge and skin of the columella with non-diluted CaHA. Injection was
performed with a cannula 22G-70mm and a volume of 0.3 ml injected in nasal bridge and 0.2 ml in columella
(A and B show patient before the procedure). A slight blanching in the upper lip area was observed after the
procedure. The patient did not report any pain but had received local anesthesia. A reticulate livedo and
cyanosis in the upper lip was observed 2 h after the procedure (C and D). The patient was diagnosed with
Day 0 Day 1 Day 2 Day 3 Day 4 embolism of one of the branches of the upper labial artery. The patient received hyaluronidase injection
1500 IU at a standard dilution of 2 ml of 0.9% NaCl solution and sildenafil 100 mg. The following day the
patient complained of swelling, reduced sensitivity of the upper lip and blueness in this area (E). A further
dose of sildenafil 100 mg was prescribed. On the third day after the procedure the patient complained of
burning mucosa, increasing swelling, decreased activity of the lip, and numbness of the tip of the nose (F–
H). Taking into account the negative dynamics, the following treatments were assigned: hyperbaric oxygen
therapy (1 procedure lasting 30 min); hyaluronidase 1500 IU injections in the columella and upper lip (0.5
Day 5 Day 6 Day 23 Day 37 Day 51
ml); intravenous infusion of pentoxifylline 400 mg per 250 ml of 0.9% NaCl solution for 1 h; dexamethasone
Figure 4 intramuscular injection 12 mg; Solcoseryl® gel on the lip mucosa; and sildenafil 100 mg once daily. On the
Sequence of events in the development of vascular necrosis (courtesy of David Funt). The patient suffered a fourth day after the procedure the patients dynamics were more positive. The skin of the upper lip was pale
facial artery embolization with ischemia of the ala following injection in the nasolabial fold, near the pyriform pink, and swelling had decreased (I). The treatments above were repeated on days 4 and 5 after which the
aperture, with CaHA using a sharp needle. Initially she was treated with massage, warm compresses, oral lip had greatly reduced in volume, skin was light pink in color, the mucosa was restored to its pink coloring,
sildenafil 50 mg daily for 4 days, nitroglycerin paste for 4 days, oral antibiotics, valaciclovir prophylaxis, and numbness of the lips had decreased (J). The patient was actively observed for 2 weeks until there was
and open treatment with aquaphor and twice-daily showering. This demonstrates that early debridement complete resolution of the signs of ischemia.
should be avoided because patients usually heal better than initially anticipated.

Injectors should also be aware of the potential for venous obstruction as a result of compression when excessive
amounts of filler are placed in a small area. Venous obstruction is generally associated with a dull, aching pain and
swelling, and a dark discoloration of the affected area, and can easily be misinterpreted and dismissed as early
discomfort and bruising after treatment.62

166 chapter 9 167

 Management of vascular compromise and impending tissue necrosis Early presentation – treatment follow-up

Early presentation – acute treatment (up to 6 hours after onset of symptoms, Figure 3) If after 6 hours circulation remains poor, hyaluronidase, aspirin, tadalafil, and the prednisolone tapering course should
be continued. There is also a number of additional therapeutic measures that can be considered that may improve
The goal is to rapidly re-instate blood flow and increase vasodilation in the affected area so treatment should outcome of CaHA induced impending necrosis.
commence without delay. Many of the steps will follow those recommended for impending necrosis after injection of
a hyaluronic acid based product.10–13 • Additional STS injection
• Without signs of severe necrosis, secondary infection is unlikely and systemic antibiotics are not necessary.
In the presence of immediate pain and/or skin discoloration, or as soon as the injector suspects the blood supply has • With signs of severe necrosis (large surface area of blanching and livedo reticularis, systemic antibiotics as well as
been compromised, the injection must be stopped immediately and, if possible, aspiration of the product should be topical antibiotics are recommended. Some authors advised antibiotics with a strong microbiological action like
attempted before withdrawing the needle. Measures should then be implemented to improve blood flow and tissue ciprofloxacin or clarithromycin.
oxygenation. Warm compresses should be applied and the area massaged to promote vasodilation and perfusion, • There was no consensus on the use of antibiotics with anti-inflammatory properties like doxycycline to treat CaHA
especially if a limited amount of CaHA (0.1 ml or less) is intravascular. Larger volumes of emboli could potentially induced ischemia as there is no published evidence to support this.
increase the extent of blocked capillary network. • Pentoxyfilline (Trental®) 400 mg three times daily may accelerate healing of soft tissue necrosis by improving
The area where the circulation of blood supply appears to be reduced should be flooded with hyaluronidase erythrocyte flexibility and increasing tissue oxygen levels.69
regardless of the filler type, due to its edema-reducing63,64 and anti-inflammatory properties.65 The amount of • Hyperbaric oxygen therapy (oxygen therapy under pressure) should be considered.65,70 This has the potential to
hyaluronidase will depend on the volume of CaHA injected. The hyaluronidase may be injected directly into the deliver oxygen deep into the skin to oxygenate ischemic tissue, reduce edema, and promote angiogenesis. It
affected site. There was strong consensus for high doses (600U of hyaluronidase for every 0.1 ml CaHA) intravascular, should be initiated in those cases where the involved tissue appears dusky the day after the event despite the
with aggressive treatment in the early stages following a vascular event. It is also important to check the reperfusion institution of the above measures (Figure 5).
every 30-60 minutes post-hyaluronidase treatment. If no improvement (e.g., less blanching, improvement of capillary • Another procedure that has been used successfully to promote healing of necrotic tissue is the use of platelet-rich
refill) is seen within 60 minutes, additional quantities of a hyaluronidase should be injected every 2 hours (repeat plasma (PRP). PRP therapy involves drawing blood from the patient, running it through a centrifuge to obtain a
3-4 cycles). plasma fraction with a concentrated platelet count and high levels of cytokines and growth factors, which are
re-injected at the site of tissue injury. PRP has been shown to improve healing of wounds, tendons and bone.71
Sodium thiosulphate (STS) has been shown to dissolve subcutaneously injected CaHA in an animal study.66 While still In one case report, PRP was injected intradermally and applied topically to the skin of a 46-year old female who
experimental, positive results have also been observed when STS was used to dissolve CaHA nodules in a patient had developed necrosis on the glabella, forehead and dorsum of the nose after injection of hyaluronic acid filler
following an aesthetic procedure.67 STS may therefore have a place in the acute treatment of CaHA vascular 2 days previously.72 The patient was initially treated with hyaluronidase, oral antibiotics and prednisolone, which
complications although there is no evidence to date in the published literature. As risks of side effects due to this could not prevent deterioration of the wound. After debridement the patient received PRP on the fourth day after
compound are negligible, we have incorporated the use of STS into the management algorithm.67 STS comes in 10 ml the onset of the adverse event. Although the patient required several treatments with a carbon dioxide laser, the
vials containing 2.5 g STS. We recommend injecting up to 10 ml of STS in the areas showing signs of ischemia. combination of PRP with standard treatments for tissue necrosis appeared to accelerate scar resolution.
• Red light therapy, for example with a 640 nm light emitting diode (LED) red light source, can be used to decrease
Aspirin should be used to limit platelet aggregation, clot propagation and further compromise, but should be given inflammation. This has been shown to improve vascular circulation and promote wound healing for necrosis
with an antacid regimen for stomach protection. The recommended immediate treatment is with 625 mg (USA) or following breast reconstruction surgery,73 and may be beneficial for impending filler-induced tissue necrosis.65
500 mg (Europe, Canada) enteric-coated aspirin.8 This should be followed by a maintenance dose of 75 mg (USA) and • One of the consensus authors (S. Fabi) indicated that monopolar radiofrequency with a rolling method may be
100 mg (Europe) for 3-5 days. Drugs such as sildenafil and tadalafil can be used to induce smooth muscle relaxation, beneficial in dilating blood vessels, but as there is no published evidence on this, radiofrequency is not included in
dilate blood vessels and increase blood flow.14 Subcutaneous injection of a low molecular weight heparin such as the algorithm.
nadroparin (Fraxiparine) can be used to prevent thrombus formation proximal to the embolus and should be injected
within 4 hrs of the intravascular event.38 All patients should be monitored closely for progress and for signs of infection. They must strictly avoid exposure to
nicotine either from smoking tobacco, vaping, patches, or second hand smoke. They should also avoid exposure to
Consensus was not achieved on the application of topical nitroglycerin paste to facilitate vasodilation. Topical extreme cold as compromised tissues are more prone to frostbite injury.
nitroglycerin may reduce tissue necrosis as a result of its vasodilatory properties with the amount dependent on the
size and area of impending necrosis. However, animal studies have noted no improvement in perfusion after topical Two of the consensus authors (D. Funt and Y. Yutskovskaya) have included case reports in this article describing the
application of nitroglycerin paste.68 In addition, application is not without side effects, such as headaches, development of necrosis following injection of CaHA for nasolabial fold augmentation and nasal bridge contouring
hypotension, and dizziness. Coadministration of phosphodiesterase inhibitors with nitroglycerin is contraindicated as and their resolutions with a combination of the procedures described above (Figures 4 and 5).
it can result in severe hypotension. At this time no clear recommendations can therefore be made.

There was strong consensus for a tapering course of oral corticosteroids such as prednisone if tissue edema is present Delayed presentation
with a suggested starting dose of 50 mg, tapering the dose every other day for a maximum of 7 days. Consensus
members mention that even though edema is reduced using corticosteroids, there is no evidence that they have a Impending vascular compromise is not always recognized immediately and some patients may present themselves
positive effect on the outcome of ischemia after CaHA injection. There was also consensus on prescribing more than 24 hours after the initial event. Treatment is still warranted as any attempt to increase vasodilation and
prophylactic antiviral medication such as valaciclovir in patients with a history of herpes simplex virus and if the reduce inflammation will improve the outcome. An aggressive therapy is required to re-establish new vessel formation
affected tissue involves the oral or nasal mucosa. and tissue oxygenation. In addition to the acute treatments highlighted in Figure 3, patients should receive daily

168 chapter 9 169

 discussion and further considerations
hyperbaric oxygen therapy sessions for 1-2 weeks. PRP therapy may need to be continued weekly for several weeks to In this document, a group of international physicians with expertise in the treatment of dermal filler complications
improve skin texture and to soften the edge between the damaged and undamaged areas. At later stages this may be collaborated to develop a consensus on the management of vascular compromise following treatment with CaHA
combined with micro-needling, or laser therapy. Meticulous wound care including regular wound cleansing and based on their collective clinical experience and the published literature. Although it remains rare, all physicians
gentle debridement of the necrotic tissue is essential to reduce healing time and limit scar formation. should be equipped to recognize and manage this event either as a result of a treatment performed in their own
practice, or when dealing with patients referred to them for an adverse event resulting from a treatment elsewhere.
The availability or doses of some of the treatments outlined in this consensus may vary by country, and while the
Treatment of open wounds consensus document outlines the key steps to follow, treatments may have to be adapted to what is locally available.
What is essential is that diagnosis is rapid and treatment is initiated immediately to limit tissue necrosis.
The presence of necrotic tissue in a wound is a physical impediment to healing and a medium for bacterial growth. If
dried serum or other debris is present it should be removed and clearly necrotic tissue debrided. Debridement should While massage is generally recommended as one of the first steps following accidental intra-arterial injection to
be conservative never removing questionable tissue as the final outcome is generally better than anticipated (Figure 3). encourage blood flow and remove any obstruction, consensus members warned that consideration should be given to
Consensus was not achieved on the type of antibiotic. Some members felt therapy should be instituted with an agent the volume of injectate. With volumes of CaHA less than 0.1 ml distribution over a larger capillary network and into
that is of benefit for its anti-inflammatory effects as well as to prevent secondary infection, such as a tetracycline (e.g. the venous system is likely to be beneficial. However, massage of bolus volumes greater than this might distribute the
doxycycline), and others that one with a strong antimicrobial action was required such as ciprofloxacin. Yet others embolus over a larger capillary network increasing the area of compromised tissue. Therefore, as a preventative
believed antibiotics should only be prescribed if there are severe signs of necrosis. If therapy is initiated, a switch to precaution, consensus members advise to limit bolus injection to 0.1 ml. If boluses of >0.1 ml were injected into an
another antibiotic may be required after culture results. In addition to regular debridement of necrotic tissue, routine artery, massage should be delayed until treatments to dilate arteries have been administered.
wound care should involve adequate hydration, daily dressings, and monitoring for secondary infection. These steps
could be performed in conjunction with hyperbaric oxygen therapy once or twice daily to improve ischemia and Hyaluronidase is recommended for impending vascular compromise regardless of whether an HA or CaHA filler was
reduce tissue loss. Open therapy with a bland ointment may be preferable initially as it allows daily cleaning of the used because of its edema-reducing properties, effects on capillary permeability and anti-inflammatory properties, all
wound with running water. Specialized dressings, such as those made of soft silicone film (e.g. Mepitel Film) or of which combine to increase blood flow to the affected area and promote wound healing. While large volumes of
hydrocolloid gel sheets (e.g. DuoDERM), maintain a moist environment and support autolytic debridement and can be hyaluronidase could also increase pressure on the tissue, consensus members believe that in reality this would be very
changed every 2 days. They are designed to protect fragile and sensitive skin and minimize risk of skin breakdown and limited and lymphatic drainage would remove most of the additional fluid from the affected area.
should be applied until re-epithelialization is complete. Care must be taken with closed dressings to avoid the risk
of superinfection. Until recently, hyaluronic acid fillers were considered to be the only fully-reversible fillers by virtue of hyaluronidase
digestion. However, a recent proof-of-concept study in a porcine model has demonstrated the potential reversibility of
For open wounds that aren’t healing properly, PRP therapy may be useful for bringing a higher concentration of CaHA by intralesional injection of sodium thiosulfate (STS).66 A follow-up study has shown that intralesional STS also
platelets to the wound site and fighting infection. Some case reports have described success with adipose-derived dissolved CaHA nodules that developed after injection of CaHA for aesthetic use.67 The dissolution of CaHA releases
stem cell therapy harvested from each patient's abdominal subcutaneous tissue for treating skin necrosis after calcium and phosphate ions, which are safely removed via the body’s normal physiological excretory processes.
filler injection.74,75 While the above study used STS to dissolve CaHA nodules, it is conceivable that intravenous STS could be used to
dissolve CaHA emboli in the vascular system. Intravenous injection of STS is indicated for the treatment of acute
cyanide poisoning and for the treatment of calciphylaxis. The latter is an uncommon disease with intravascular
Treatment of closed wounds calcification of the intima leading to luminal thrombosis, as well as variable extension into the overlying dermis.77 The
nodular or plaque-like subcutaneous calcifications and painful tissue necrosis often lead to ulceration and secondary
Due to the replacement of normal tissues by fibrous material, the healing process may result in scar formation in spite infection. Infusion of STS 3 times weekly (25 g IV over 30 to 60 minutes), has been shown to significantly reduce
of debridement and aggressive dressing changes. Scars often cause contracture and subsequent cosmetic calcifications in the affected areas.78 For acute cyanide poisoning the infusion rate is faster; 25g in 5-10 minutes, due
disfigurement, which results in a traumatic burden to the patient. Dressings that keep the wound moist should to the acuteness of the situation. This promising potential treatment for CaHA-induced skin necrosis or vascular
continue to be used until it is completely healed. A number of different types of lasers have been used to improve scar occlusion leading to vision loss is currently undergoing further study, but may form part of future algorithms when
appearance including: pulsed dye laser, nonablative fractionated laser resurfacing, and fractionated laser resurfacing.65 further data on dissolving time of the CaHA particles, optimal method of administration, and systemic safety have
been established.
Micro-needling (collagen induction therapy) may be considered to improve healing and reduce scar formation. This
technique uses fine needles to puncture the skin at various depths to create a controlled skin injury without damaging
the epidermis.76 Each puncture creates a channel in the dermis that stimulates the release of growth factors and
cytokines. In turn, these stimulate new collagen and elastin production along with angiogenesis. A number of
automated micro-needling devices are available including dermal rollers and the more recently developed dermal
stamps or pens. Micro-needling can also be combined with other treatments including growth factors, vitamin C and
PRP to enhance its skin rejuvenation properties. It is recommended to repeat treatment at 4-week intervals. Patients
should be advised that the full cycle of collagen production is a slow, multistage process that can take up to 10 months
to achieve final results.

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secondary to cosmetic facial filler injection. Ann Plast filler delivery after tumescent injection. PRS Global Open.

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 10
Consensus on the use
of hyaluronic acid fillers
from the cohesive
polydensified matrix
range: best practice in
specific facial indications

First author.
Van Loghem JAJ1, Sattler G2, Casabona G3, Cotofana S4, Fabi SG5, Goldie K6, Gout U7, Kerscher M 8, Lim TS9,
Pecora C10, Sattler, S2. Trindade de Almeida A11, Wantiphakdeedecha R12, Werschler P12. Pavicic T9.

Final draft, document under final review. Target journal: Clin Cosmet Investig Dermatol

1. UMA Institute, Falckstraat 51, Amsterdam, Netherlands and Department of Ophthalmology, Orbital Center,
2. Rosenpark Clinic, Darmstadt, Germany
3. Academic Scientific Department, Ocean Clinic, Marbella, Spain.. Clinical Research in Marbella, Spain
4. Department of Medical Education, Albany Medical College, Albany, NY, USA.
5. Cosmetic Laser Dermatology, San Diego, CA, USA.
6. European Medical Aesthetics Ltd, London, United Kingdom.
7. LAM, London, United Kingdom.
8. Division of Cosmetic Science, Department of Chemistry, University of Hamburg,Hamburg, Germany.
9. Clique Clinic Petaling Jaya, Selangor, Malaysia
10. Dermatologie-Clínica, Cirurgia, Cosmiatria e Laser, São Paulo, Brazil.
11. Clínica Dermatológica do Hospital do Servidor Público Municipal de São Paulo, São Paulo, Brazil.
12. Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
13. Premier Clinical Research, Spokane, WA, USA.
14. Private Practice for Dermatology and Aesthetics, Munich, Germany.

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 summary
HA fillers play an increasingly important role in minimally- The tissue layers into which these products are placed and the
invasive aesthetic procedures and a wide range of products manner in which they are injected has a significant effect on
is now available to physicians. The CPM-HA range has been treatment results. Based on the anatomical landmarks, specific
developed to allow physicians to tailor their treatments with treatment techniques have been suggested to reduce the risk of
products that have optimal rheological properties for a defined serious adverse events, and in particular arterial embolization.
tissue indication from deep volumizing to skin revitalization. This consensus document has been prepared to guide physicians
The range is characterized by several differentiators. The in the selection of products, administration techniques and
cohesive polydensified matrix (CPM) crosslinking technology depths of injection for the specific indication with the aim of
enables products to be produced with different proportions of optimizing aesthetic outcomes, safety and patient satisfaction.
crosslinking density, and which provides the range with the It is anticipated that injectors will use the knowledge in this
cohesivity required for excellent tissue integration. In the case document to individualize treatments for their patients and thus
of CPM-HA S and CPM-HA B, the blanching technique allows achieve optimal aesthetic outcomes.
product to be placed very superficially. The high cohesivity
of CPM-HA I provides it with resistance to dynamic stress
making it ideal for lifting and contouring, and the high elasticity
and plasticity of CPM-HA V make it ideal for volumizing
and projecting.

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 introduction
Hyaluronic acid (HA) injections are one of the top aesthetic procedures performed worldwide and an essential part of of indications and injection depths, but injectors new to the range may be unsure of the optimal product and injection
modern aesthetic practices. Unmodified HA has a half-life of only 24-48 hours in tissue, making it unsuitable for use technique for specific facial areas. Furthermore, the safest injection layer and technique depends on the anatomy
as a dermal filler. However, synthetically cross-linking the HA improves stability, longevity, and viscoelastic properties of the area. It is not possible to cover every facial indication in a single publication and so to provide most value to
[Falcone & Berg, 2008]. A number of HA manufacturers have used their proprietary crosslinking technologies readers, this expert panel was convened to provide recommendations on the most appropriate CPM-HA product,
to develop ranges of HA fillers suitable for specific facial indications, tissues and injection depths. Cohesive injection techniques and depths of injection for the more challenging facial aesthetic indications.
polydensified matrix (CPM) is the crosslinking technology used for the broad and diverse Belotero® HA range, which
includes Belotero® Soft (CPM-HA S), Balance (CPM-HA B), Intense (CPM-HA I), Volume (CPM-HA V), Belotero®
Lips Contour (CPM-HA LC) and Lips Shape (CPM-HA LS), and the most recent addition Belotero® Revive containing Consensus methodology
additional glycerol (CPM-HA R); with the exception of CPM-HA R, all are also available with lidocaine. Each product
differs in its degree and manner of HA crosslinking, HA concentration and molecular weight to influence four key The consensus statement was developed by drawing on the combined expertise of 14 experts with an average of 17.5
rheologic properties that predict treatment results: cohesivity, elasticity, viscosity, and plasticity (Table 1). The benefits years’ experience in aesthetic medicine and 8 years’ experience with CPM HA products, including dermatologists,
of a portfolio of HA products for the physicians are that they are able to tailor their treatments to specific indications aesthetic physicians, and an expert in facial anatomy. In April 2019, consensus members gathered for a full day
and safely combine products from the same portfolio. meeting and were tasked with achieving “best practice in specific facial indications” based on local facial anatomy
and individual product attributes. Each expert was responsible for presenting one facial area, and to facilitate the
consensus process the results of a pre-meeting questionnaire summarized the preferred product(s), injection volumes,
depths and techniques of the group.
Table 1
A consensus was defined as agreement from more than 75% of participants, with majority agreement denoted
by agreement from >50-75% of experts, consensus by >75-95%, and strong consensus by >95% of participants.
CPM-HA R CPM-HA S CPM-HA B CPM-HA I CPM-HA V CPM-HA LC CPM-HA LS
Statements are presented as recommended if they are supported by published clinical evidence or suggested
HA content / 20 mg/ml HA; 20 mg/ml 22.5 mg/ml 25.5 mg/ml 26 mg/ml 22.5 mg/ml 25.5 mg/ml if based on the experts’ practical experience. All recommendations given here had a strong consensus unless
other active 17.5 mg/ml with/without with/without with/without with/without Lidocaine Lidocaine
ingredients glycerol Lidocaine Lidocaine Lidocaine Lidocaine 0.3% 0.3% otherwise indicated.
0.3% 0.3% 0.3% 0.3%

General recommendations for safe injection techniques and avoidance of complications

Uses Skin Superficial Medium Deep lines; Improvement Lip contour; Lip volume;
revitalizing lines to deep volume of facial mild oral severe oral
lines; lip and lip volume loss commissures commissures Regardless of the technique and area of the face being treated sterile technique must be employed. Skin should be
enhancement augmentation cleaned and disinfected and the areas re-treated if contaminated. The needle or cannula used should be changed if no
longer sterile. Injections should not be performed through infected or traumatized skin.

Cohesivity ++++ ++++ +++++ +++++ ++++ +++++ +++++

To reduce the risk of intravascular penetration, injections should be performed with low plunger pressure and in small
Elasticity + + +++ ++++ +++++ +++ ++++ aliquots. In addition, perpendicular (not parallel) orientation of the needle or cannula to the direction of the arteries
is recommended. All injections should be performed with a moving needle as even if within a vessel, only minimal
Viscosity + + ++ +++ ++++ ++ +++
material will be deposited. The injector should advise the patient to inform them immediately if pain is felt during the
Plasticity - - ++ +++ ++++ ++ +++ injection as this may be a sign of vessel penetration or ischemia. The injector should also focus on the needle tip to
watch for blanching. Patients should be advised to return to the physician’s practice immediately if they experience
Properties of Cohesive Polydensified Matrix/Hyaluronic Acid Formulations. pain or bluish coloration in the first days after injection. Hyaluronidase should be available in every physician’s office.
Injecting with a blunt cannula of 25G or larger may further reduce the risk of an intravascular injection[Pavicic et
al, 2019a].

Why is this expert consensus required in aesthetics?

The popularity of HA filler injections among patients seeking non-invasive methods of facial rejuvenation combined
with the variety of HA filler products available requires physicians to be familiar with all available preparations
in the range and confident about which product is optimal for a particular indication. The CPM-HA range is one
of the largest HA filler ranges currently available and uses a second crosslinking step to produce a range of fillers
with variable densities of crosslinking (CPM technology). This technology allows products to be designed that are
compatible with the tissues into which they are injected by adjusting the key rheologic properties: cohesivity,
elasticity, viscosity, and plasticity [Sundaram & Cassuto, 2013] leading to an optimal tissue integration and projection
capacity [Tran et al, 2014; Gavard Molliard et al, 2016]. Each product in the CPM-HA portfolio has a rheologic
balance of cohesivity, elasticity, and plasticity and has been specifically designed to address a different spectrum

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 introduction
Upper Face Indications

Forehead

Landmark deficiencies
The aesthetic unit of the forehead is defined by the hairline superiorly, temporal crest laterally and the supraorbital
rim inferiorly [Sherris & Larrabee, 2009]. Patients may seek aesthetic treatment for a number of forehead landmark
deficiencies including suprabrow volume loss (frontal concavity), a prominent brow ridge, loss of forehead convexity,
deep horizontal forehead lines, vertical glabellar lines, and diagonal sleeping lines; loss of temporal volume is
considered in the section below. While botulinum toxin is effective at reducing glabellar and forehead lines, it will be
less effective in foreheads that require volumetric augmentation and in subjects with visible wrinkles at rest [Anido et
al, 2017]. Figure 1
Forehead entry points and treatment zone. Black lines: limits of the forehead area
The shape of the forehead is primarily determined by the shape of the underlying frontal bone, which loses its (temporal crest, hairline, supraorbital rim) and limits of the arterial danger zone
convexity with age [Frank et al, 2018]. This may be combined with volume atrophy of the deep fat pads of the upper (1.5-2.0 cm superior to the supraorbital rim). Black dots: entry points. Lines from
forehead, the middle and central forehead fat pads, retro-orbicularis oculi fat (ROOF), brow fat pads, and lateral black dots: retrograde linear threads of 0.025-0.04 ml CPM-HA I or CPM-HA V
temporal cheek fat pads [Cotofana et al, 2017]. This deep and subcutaneous volume influences the shape of the with a 22G cannula, bevel directed towards the periosteum. Dotted black lines:
forehead, brow position, surface smoothness of the forehead skin, and the type and configuration of forehead wrinkles optional additional retrograde linear threads.
(vertical and horizontal), all of which affect how old and attractive a person looks.

Anatomical considerations Product choice will depend on factors such as the severity of the concavity and patient characteristics including skin
The arteries of interest in the forehead area are the supratrochlear and supraorbital arteries and their branches, as thickness and degree of skin laxity. Treatment should therefore be tailored to the individual patient. Options include
well as the frontal branch of the superficial temporal artery that connects to the supraorbital artery [Cotofana et al, CPM-HA I, which has good projection capacity and does not migrate easily, and CPM-HA V, which is easy to shape.
2017]. The supratrochlear and supraorbital arteries travel upward under the frontalis muscle until approximately 1.5- In some older patients with thin skin CPM-HA B may also be an option. CPM-HA I and CPM-HA-V are injected with
2.0 cm above the orbital rim (a line correlating to the middle frontal septum) [Cotofana et al, 2017] when they pass a 22G cannula with 0.025-0.04 ml/thread, bevel directed towards the periosteum. It can be difficult to truly be in the
through the muscle and become more superficial as they approach the hairline. In the upper forehead the arteries lie supraperiosteal plane initially, and even when in that space, it is possible to change planes easily and injectors should
in a subcutaneous plane and if injecting in the supraperiosteal plane, three layers of tissue will separate the tip of the ensure that the cannula tip does not shift position during injection. Large boluses are not recommended when using
cannula from the arteries: fascia, fat and frontalis muscle [Cotofana et al, 2017]. CPM-HA I as the product is harder to mold after placement.

Some group members use sharp needles for forehead injections, but no more than 0.025 ml of product should be
injected per bolus or retrograde linear thread. This is based on information from a cadaver study which estimated
that the average volume of the supratrochlear artery from the glabella to the orbital apex was only 0.085 ml with a Table 2
spread to 0.04-0.12 ml in six cadavers [Khan et al, 2016]. Others felt strongly that only blunt tip cannulas, at least 25G
diameter, should be used for forehead augmentation. Indication Product / needle Volume Injection plane Technique
or cannula size

Product and injection technique Medial frontal concavity CPM-HA V, I or 0.5 ml/side; Subgaleal Central entry point just above the frontal
Injections are placed in the supraperiosteal plane. The central entry point is in the midline at the top of the concavity B 22G cannula 0.025-0.04 concavity below hairline. Remember to
(take care of the facial vein when selecting the entry point). For the lateral forehead, recommended entry points are ml/thread palpate for superior temporal artery in
1.5-2.0 cm above the orbital rim at the temporal crest, and if necessary another lateral entry point higher towards this area
the hairline at the temporal crest (Figure 1) (Table 2). Due to anatomical constraints, blunt tip cannulea (at least 22G)
are recommended. Lateral frontal concavity CPM-HA V, I or 0.5-1.0 ml/side; Subgaleal Lateral entry points are 1.5-2.0 cm above
B 22G cannula 0.025-0.04 the orbital rim at the temporal crest;
ml/thread optional additional entry point higher
towards hairline. With lateral entry points
product should be injected in a direction
perpendicular to arteries

Recommendations for forehead augmentation and rejuvenation.

Level of consensus: strong

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 introduction
Avoidance of complications
Injectors should not apply force and respect resistance by gently rotating the syringe from side to side to advance,
instead of forcefully advancing. Injections should be limited to small volume boluses or linear retrograde threads
to avoid significant adverse outcomes like blindness should inadvertent retrograde intra-arterial embolization
occur. Injections with 30G or 31G needles are not advised when perpendicular on bone due to the possibility of
intravascular injection in supraperiosteal or periosteal arteries. When injecting with thicker needles, the product
will also distribute in more superficial anatomical layers along the injection canal due to backflow, even when
using smaller injection angles [Pavicic et al, 2019b]. The consensus was that blunt-tipped cannulas are preferred for
forehead augmentation as they reduce the risk of intravascular injection.

Temples

Landmark deficiencies
The temple is an area of soft tissue between the temporal crest and the zygomatic arch. Loss of volume in this region
may occur as a result of aging-associated changes in the underlying skeleton, redistribution of superficial and deep
temporal fat pads, temporalis muscle atrophy, and skin laxity [Juhász & Marmur, 2015]. Temporal volume loss is seen
in conditions that cause facial lipoatrophy such as HIV-infected individuals treated with highly active antiretroviral
therapy and gives the face a skeletonized look. Forehead shape is also affected by temple volume loss and vice versa.

Figure 2
Anatomical considerations Treatment of the temples. The posterior temple is divided into three zones (1-3), and injections in these
When injecting in the temporal area it is important to be aware of anatomical landmarks to ensure correct entry different zones will result in different aesthetic effects. Injection in the anterior temple (zone 4) is only
points. In this region, arteries and veins are located in superficial layers of tissue as well as in the deeper layers. required for very skeletonized faces.
The superficial temporal artery, a branch of the external carotid artery, is located inside the superficial temporal
fascia, and has connections to the supraorbital artery which is a branch of the ophthalmic artery. The anterior deep
temporal artery anastomoses with the zygomatico-temporal artery, which connects likewise to the ophthalmic artery
circulation. The middle zygomatico-temporal vein travels inside the superficial temporal fat pad and connects to the
supraorbital vein in the supraperiosteal plane of the lower forehead.

Product and injection technique

Consensus members recommended dividing the temporal region into a posterior and anterior region (Figure 2;
Table 3), and into upper and lower temporal compartments separated by the inferior temporal septum. Unless the
face appears very skeletonized, only the posterior temple is filled as this will also act to lift the middle and the lower
face [Suwachinda et al, 2018]. For filler treatment, the posterior temple is divided into three zones, and injections
in these different zones will result in different aesthetic effects (Figure 2). Injections in zone 1 will result in a lateral
brow lift, injections in zone 2 will stretch the lower eyelid and lift the anterior temple, and injections in zone 3 will
lift the lateral cheek and provide mandibular definition. Injections in all three posterior temple zones are performed
with a cannula. The use of assessment scales such as the Merz validated temple scale is useful to grade severity.
For moderate to severe superficial fat loss experts recommended CPM-HA V or CPM-HA I 0.5 ml/side with a 22G
cannula injected subdermally (for volume and lifting) or in the interfascial space (for volume replacement only);
higher volumes can be used in more severe cases (Figure 3). If the anterior temple needs volumizing, the injection
should be performed with CPM-HA V at the periosteal or interfascial level, or a very small amount in the subdermal
level. In order to correct volume deficiency with epiperiosteal injection, significantly more product will be necessary
[Cotofana et al, 2019a]. Injections with a needle should not be performed in the lower temporal compartment due to
the presence of the deep temporal arteries and the connection of the deep temporal fat compartment with the Bichat
fat of the cheek.

Figure 3
Before and after 1 ml CPM-V of the temples (other indications were treated too). Courtesy Jani van Loghem, MD

184 chapter 10 185

 introduction
Some patients may present with visible blood vessels in the temporal area. Treatment should be individualized based Superior orbital hollowness
on skin properties. In patients with very thin skin, the consensus approach for treatment was to use CPM-HA B, which
has low elasticity and viscosity as well as high cohesivity for optimal tissue integration and a smooth, even contour. Landmark deficiencies
Using a temporal crest entry point, the product is injected subdermally with a 22-25G cannula (22G is preferred for As the orbit widens during aging, the eyes will start to look hollower, often accentuated by intraorbital fat loss [Morley
safety reasons, but as the diameter is larger the product will flow more easily and more will be used per strand). A et al, 2009]. Superior orbital hollowness also known as A-frame deformity or sunken upper eyelid sulcus may be
retrograde, linear threading technique is used, injecting small amounts in multiple passes for a total volume of 0.5-1.0 genetic or associated with aging as a result of atrophy of preseptal fat in the upper eyelid [Morley et al, 2009]. Patients
ml/side. CPM-HA V is preferred for normal and thicker skin as much less product is required. Consensus was that a with severe hollowing have very thin upper eyelid skin and little or no subcutaneous fat. The resulting hollowness of
cannula (22-25G) is preferred to perform injections in the temporal region. the upper eyelid makes individuals look older than they actually are (Figure 4).

Some experts use a sandwich technique when correcting very severe volume loss in the posterior temple, injecting
CPM-HA V for both lifting and contouring due to its high elasticity and plasticity, but no studies have been conducted
using this combination approach and further research is required.
A B

Avoidance of complications
Anastomoses of the superficial temporal artery with the supraorbital and supratrochlear arteries and of the anterior
deep temporal artery with the lacrimal artery present a risk of blindness should artery embolization occur. Opinion
was divided approximately 50:50 on whether aspiration should be recommended as some felt it would give a false
sense of security [Goodman et al, 2019]. The high viscosity of some fillers, for example CPM-HA V and CPM-HA I,
may give unreliable aspiration results if using a 27G, 13 mm needle, as a high suction pressure and long aspiration
time (up to 8 s) may be required to obtain a positive test result [Van Loghem et al, 2018]. A negative test result (no Figure 4
blood in needle hub) should therefore not be relied on due to the high probability of a false negative result. Injections Example of patient with superior orbital hollowness A: Before and B: after treatment with CPM-HA B.
in this area should be performed with a 22G blunt-tipped cannula and performed very slowly so patients can
comment on how they feel.

Anatomical considerations
In this area no major neurovascular structures are identified. However, due to the complexity and the adherence of
Table 3 the fascial layers there is an increased of penetrating the orbital septum and placement of product posterior to the
septum and inside the orbit. Thus, a more superficial (not subdermal) approach is recommended.
Indication Product / needle or Volume Injection plane Technique
cannula size
Product and injection technique
Prior to injection, the upper eyelid crease and the supraorbital rim should be marked as this is the area that should be
Posterior and anterior CPM-HA I or CPM-HA V 0.5-1.0 ml/side, higher Subdermal or Temporal crest entry point, filled (Figure 5). No product should be injected below the upper eyelid crease (Figure 5). A pre-insertion point is made
temples volume loss / 22G stiff cannula volumes may be Interfascial from frontal periosteum with a 23G needle on the lateral superior orbital rim. CPM-HA B is the preferred product as it has a low viscosity
required if volume through temporal crest and a low G prime and therefore shows good tissue integration, low hygroscopy, no discoloration and no Tyndall
loss severe; into the interfascial space. effect [Micheels et al, 2013]. Using a 25G cannula, CPM-HA B (0.3-0.5 ml/side) is placed just deep to the orbicularis
0.05-0.1 ml/thread Multiple passes injecting oculi muscle in the preseptal fat and superficial to the orbital septum, but not deeper (Figure 6) (Table 4). Very small
small amounts. amounts of product are placed per injection (max 0.025 ml) as it is impossible to massage in this area. The tip of the
cannula should not be visible during injection as this would indicate product is being placed subdermally and not in
Posterior and anterior CPM-HA B / 22 G 0.5-1.0 ml/ side; Subdermal Temporal crest entry point. the preseptal fat, which will make the lid heavier. In patients with severe hollowing, small amounts of CPM-HA I may
temples visible temporal stiff cannula 0.05 ml/thread Multiple passes injecting be used because of its lifting effect. CPM-HA S injected subcutaneously may be appropriate for less severe cases, but
blood vessels and very small amounts. is not ideal to replace lost volume.
thin skin
Consensus members advised that HA fillers were the best option to address volume deficiency, but if the hollowing
Severe anterior temples CPM-HA V / 27G Max 0.1 ml/bolus, Supraperiosteal Microbolus. results from excess upper eyelid laxity, skin tightening procedures such as a fully ablative CO2, fractionated CO2 or
volume loss or 30G needle 0.5-1.0 ml/side microfocused ultrasound with visualization (MFU-V) are indicated either alone or followed by HA filler.

Recommendations for temple contouring.

Level of consensus: strong.

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 introduction
Table 4

Upper lid fold Upper eyelid crease Indication Product / needle Volume Injection plane Technique
or cannula size
Lateral canthus Lacrimal puncta
Superior orbital CPM-HA B 25G cannula 0.3-0.5 ml/ side (0.025 Deep to the orbicularis Preinsertion point
Medial canthus
Limbus hollowness ml/droplet) oculi muscle in the made with 23G needle

Nasofacial sulcus preseptal fat and above on the lateral superior

Malar fold the levator aponeurosis orbital rim. CPM-HA I
Nasojugal crease may be used for severe
Infraorbital hollowing and CPM-HA
crease Lower eyelid
crease S for mild hollowing.
Undertreatment advised

Figure 5
Periorbital landmarks. Recommendations for superior orbital hollowness.
Level of consensus: Strong.

Avoidance of complications
Orbicularis oculi muscle (everted) Injectors should avoid injecting too close to the supraorbital foramen because of the risk of injecting the neurovascular
bundle, which sometimes has a connection to the upper eyelid. Depending on the amount of product injected, there
ROOF
Preseptal fat can be temporary swelling as HA is hygroscopic and therefore undertreatment is advised (80% correction in severe
cases where up to 0.5 ml CPM-HA B per side is injected and 90% correction in mild cases where up to 0.3 ml per
side is injected). Follow-up treatment if necessary may be performed when swelling has subsided.

Mid Face Indications

Infraorbital hollows

Landmark deficiencies
The infraorbital region can present with hollowing. However, depending on where the aesthetically unpleasing
depression is located it is termed differently. Medial to the mid-pupillary line it is termed tear trough. Lateral to the
mid-pupillary line it is termed palpebromalar groove. The V-frame deformity refers to the area located between these
two deformities and is associated with midfacial soft tissue descent. The nasojugal groove refers to the inferior end of
the tear trough which is formed by the superior margin of the superficial nasolabial fat compartment. (Figure 7) [Lee &
Hong, 2018]. With thin skin overlying bone and little to no subcutaneous fat or muscle in this region, the infraorbital
region can be a challenging region to treat due to a variety of factors: herniation of intraorbital fat, atrophy of the skin
and subcutaneous fat, contraction of the orbital part of the orbicularis oculi muscle, and malar bone resorption [Lee &
Hong, 2018]. It is also accentuated by descent of the mid-cheek.

Figure 6
Injections of superior orbital hollows. Product is placed just deep to the orbicularis oculi muscle in the
preseptal fat and above the levator aponeurosis

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 introduction

Tear trough

Palpebro-
malar groove TT =Tear trough
PMG = Palpepromalar groove
Nasojugal fold/
groove ZRL = Zygomatic retaining ligament
ZCL = Zygomatic cutaneous ligament
Figure 7 Figure 8
Anatomy of the infraorbital hollow. Treatment of the infraorbital hollows.

A B
Anatomical considerations
Recent anatomical studies indicate that the lower eyelid and lid-cheek junction should be regarded as a single
unit and influence each other during aging [Mojallal & Cotofana, 2017]. In the lateral lower eyelid, a thin layer of
subcutaneous fat can be observed, which is absent in the medial part of the lower eye lid, i.e. the tear trough [Mojallal
& Cotofana, 2017]. Malar edema is a frequent complication of the lateral infraorbital area and occurs when HA filler is
trapped between the malar septum and the skin [Funt, 2011]. Lymphatic drainage vessels become blocked, lymphatic
fluid accumulates, and the increasing hydrostatic pressure results in malar mounds. Some patients may already have
impaired lymphatic drainage, and should be treated with care or in combination with other treatment modalities.

C D
Product and injection technique
Treatment of the infraorbital hollow can be approached in three stages (Table 5). The first stage targets the zygomatic
cutaneous and zygomatic retaining ligaments by injecting a small amount of product below the ligaments into the
SOOF to orient them more horizontally, essentially lifting the cheek (Figure 8). The second stage focuses on the
palpebromalar groove (also known as the lid-cheek crease) by targeting the circular orbicularis retaining ligament
(ORL). The ORL has its origin at the orbital rim and inserts into the orbicularis oculi muscle that is attached to the skin.
With age, the orbit widens due to bone resorption and the ORL descends. Placement of filler product just below the
ORL on the periosteum can push the ORL into a more horizontal orientation and therefore reduce the palpebromalar
groove created by the ORL insertion. It also has the added advantage of lifting the corner of the eye. The choice of
product depends on patient characteristics including volume deficit and skin thickness. CPM-HA I or CPM-HA V may
be a good option for patients with thicker skin, but in patients with thin skin, CPM-HA B is the preferred product due E Figure 9
to its low elasticity and viscosity and high cohesivity which provide optimal tissue integration properties. CPM-HA B Clinical photo series of 3 stages of
is injected with a 22-25G cannula as close to the retaining ligament as possible from an insertion point lateral to the IOH treatment. Courtesy Dr van Loghem.
orbicularis oculi skin insertion (Figure 9 [Dr van Loghem to provide clinical photo series showing the different steps). A. Lateral Cheek (CPM-V);
Another option is to choose the same insertion point as for the tear trough close to the midline, just laterally from the B. Medial Cheek (CPM-V);
angular vein, with the cannula directed towards the lateral epicanthus. Thereby, a small amount of product can be C. Palpebromalar groove (CPM-I);
placed below the lateral orbital thickening to increase the lateral lifting vector. The size of the cannula and injection D. Tear trough (CPM-B);
plane remain the same (see above). In patients with very thin skin, CPM-HA S may be used to disguise dark shadows. E. Result immediately after left side treated.
Note the canthal tilt improvement.

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 introduction
The third stage of treatment targets the tear trough, which is located between the ORL and the nasojugal groove. Avoidance of complications
The tear trough is treated by placing CPM-HA at the supraperiosteal level in between the tear trough ligament and the To avoid malar edema, injections in the SOOF should always be placed periosteally [Funt, 2011]. Patient selection is
angular vein, going as far medially as anatomy allows. At this point there is an attachment of the tear trough ligament key. They should be asked if they wake up with swollen eyelids in the morning; if so they are not suitable candidates
to the bone prohibiting further advancement and the cannula is advanced more superficially in the subdermal layer for this procedure because of an increased risk of malar edema, which is difficult to resolve. Always undercorrect by
in order to reach the medial part of the tear trough. The consensus was for CPM-HA B (due to its optimal integration up to 10-20%. Patients with moderate and severe skin laxity (“positive pinch test”) or fat herniation should be treated
properties in this very delicate area) injected with a 25G cannula or larger. When injecting the tear trough, it is with other suitable modalities; filler injections must be avoided in these patients.
important to stay deep on the periosteum and only inject small amounts of product totalling 0.1-0.5 ml/side.
Some consensus members also recommended injecting with CPM-HA S in the subcutaneous layer.
The treatment of the IOH may be performed in two sessions, the first covering the palpebromalar groove, and the Pre-auricular hollowing
second the tear trough.
Landmark deficiencies
Pre-auricular hollowing is the area anterior to the ears and has as superior boundary the zygomatic arch (diagonal
cheekbones in women, more horizontal in men), and as inferior boundary the jawline (Figure 10). It is an important
Table 5 aesthetic landmark and an outward statement of health and sexual dimorphism. Pre-auricular flattening or loss of
concavity may also occur post-facelift. The area of shadow differs in men and women and is typically ovoid in
Indication Product / needle or Volume Injection plane Technique women and triangular to square shape in men.
cannula size When treating this area there are therefore two objectives: to create shadow with cheek augmentation and to correct
excessive hollowing and wrinkles when there is age-related volume loss.
Stage 1 CPM-HA I or CPM-V 0.5 ml/side; 0.05-0.1 Periosteal at the Injection below zygomatic
Zygomatic cutaneous 22-25G cannula ml/bolus origin of the ZRL cutaneous and zygomatic
(ZCL) and zygomatic and ZCL retaining ligaments
retaining ligaments to reposition them
(ZRL) more horizontally Topographical Anatomy:
Pre-Auricular/Sub-Malar Hollowing

Stage 2 CPM-HA B 23-25G 0.2-0.5 ml/side; Periosteal Target palpebromalar groove

Palpebromalar cannula. Some 0.025-0.05 ml/thread inferior to the orbicularis
groove recommended CPM-HA retaining ligament. Insertion
I or CPM-HA V† point lateral to orbicularis oculi The mid cheek In women, this
muscle skin insertion
ideally has a slight concavity classically
concavity, resulting has an ovoid shape.
Or for the alternative entry point
in a low-light In men, the shape tends
up to the lateral "shadow" from the to be more square or
orbital thickening zygoma above. rectangular.

Stage 3 CPM-HA B 25G cannula. 0.1-0.5 ml/side; Periosteal Injections are placed deep on
Tear trough Some recommended 0.025-0.05 ml/thread (CPM-HA B) the periosteum between the
CPM-HA S† Max 0.1 ml/side of Subcutaneous ORL and zygomatic cutaneous
CPM-HA S if injected (CPM-HA S) ligament taking care to stay Figure 10
subcuanteously below malar septum and only Pre-auricular hollowing: landmark deficiencies illustrating midface borders
inject small amounts

Anatomical considerations
This area is not a particular danger zone for subcutaneous or subdermal injections, but deeper injections may enter
Recommendations for infraorbital hollows. the parotid gland, Stenson’s duct and various veins that course over the masseter. Arteries in this area also run deep
Level of consensus: Strong. †Recommended by 3 experts +1 for CPM-V and include the external carotid artery, transverse facial artery, and maxillary artery, as do the facial nerve and
its branches.

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 introduction
Product and injection technique Avoidance of complications
For volumization of the hollow all experts recommended CPM-HA V due to its high elasticity and viscosity. The In addition to deep vessels such as the transverse facial artery, a branch of the superficial temporal artery, the parotid
product should be molded to the desired shape immediately post injection and to ensure a smooth transition between gland lies below the subcutaneous fat, deep to the injection plane, and should be avoided as intraglandular injection
treated and untreated areas. CPM-HA V is injected with a 22G or 25G cannula subdermally with a retrograde fanning can result in parotitis. In the medial portion, care should be taken to avoid the facial vein.
technique (Table 6). The aim is to correct the depression, but not to create convexity.
To create pre-auricular hollowing a vectoring approach is used to augment and lift across the zygoma taking care to
create a more ovoid hollowing in women and more geometric (sharper defined) hollowing in men (Figure 11). Radial cheek lines

Landmark deficiencies
Static radial cheek lines occur with aging as a result of soft tissue migration, bone resorption, fat atrophy of the buccal
and lateral cheek fat pads and laxity of the fat pad boundaries, loss of skin elasticity, and SMAS contraction [De
Almeida et al, 2017]. The different deficiencies lead to three different classes of radial cheek lines. Type 1 lines are due
to structural deficiencies related to bone resorption and atrophy and redistribution of the fat pads. Type 2 lines are due
to skin laxity resulting from a loss of collagen and elastin as a result of extrinsic and intrinsic skin aging. Finally, type 3
lines are due to a combination of the above (Figure 12). It is important to analyze the patient carefully to determine the
underlying cause as the different deficiencies require individual treatment approaches.

Figure 11
Creating mid-face hollowing.

1: Type 1 lines: structural deficiencies 2: Type 2 lines: skin laxity 3: Type 3 lines: structural deficiency plus skin laxity

Table 6 Figure 12
Types of radial cheek lines.
Indication Product / needle or Volume Injection plane Technique
cannula size

Pre-auricular CPM-HA V 22-25G 0.1-0.5 ml/side; Subdermal Retrograde fanning technique. To create
hollowing cannula 0.05-0.1 ml/thread pre-auricular hollowing a vectoring
approach is used to augment and lift
across the zygoma taking care to create
a more ovoid hollowing in women and
sharper hollowing in men.

Recommendations for pre-auricular hollowing.

Level of consensus: Strong

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 introduction
Anatomical considerations Product and injection technique
Radial cheek lines are lines ingrained into the face at rest by habitual expressions. An etiological understanding Radial cheek lines occur in highly dynamic areas and so resilience of the product is very important. Type 1 lines
of fine lines provides the rationale for addressing them with HA fillers. Age-related volume loss occurs at multiple require lifting and volume augmentation to reduce the wrinkles for which CPM-HA I and CPM-HA V have the ideal
levels, involving bone, subcutis, dermis and epidermis, it is therefore important to assess the patient for their need for rheologic properties (high elasticity and plasticity) (Table 7). Treatment begins in the lateral cheek with supraperiosteal
layered volumization. injection of two small boluses of CPM-HA I (0.2 ml/injection point) with a 27G needle or 22-25G cannula to enhance
bone support over the zygomatic arch (Figure 14). To volumize the medial cheek, CPM-HA V is injected in the deep
Recent anatomical studies have described the boundaries of the superficial and deep fat compartments [Cotofana medial cheek fat pad using a 22-25G cannula (some preferred 22G because of proximity of facial vein and infraorbital
et al, 2017] and demonstrated that they behave differently on injection of filler material [Schenck et al, 2018]. vessels) and 1.0-1.5 ml of product per side with a fanning technique (Figure 14).
For example, whereas the inferior aspect of the middle cheek fat compartment descended on filling, this was not
observed for the superficial medial cheek (malar fat) compartment, lateral cheek, and both superficial temporal
compartments, which produced a lifting effect when filled. To take advantage of these different effects, the
boundaries of the different compartments must be respected when performing filler injections (Figure 13).

Figure 14
A 32-year old patient with radial cheek lines caused by lack of bone support but no photodamage (type 1 lines). In a single session,
treatment with two small boluses (0.2 ml) of CPM-HA I supraperiosteally on the cheekbone and 1 ml of CPM-HA V injected
subcutaneously with a fanning technique will improve the situation.

In patients with type 2 lines, the approach is dermal volume replacement and hence improved tissue quality,
including skin elasticity, texture, and reflectance [Sundaram et al, 2015]. CPM-HA B is injected with a 30G needle
using the blanching technique [Illustration of blanching technique to be added] [Micheels et al, 2013] with multiple
punctures. The total volume injected will vary according to the severity of the lines, but will range from 0.5-1.0 ml/
side. In patients with very thin skin or very superficial lines CPM-HA S (0.5 ml/side) may be preferred combined with
neurotoxin treatment of the platysma [De Almeida et al, 2018].

In some cases a combination of CMP-HA B injected with a 30G needle and CPM-HA S injected with the INViSIBLE
NEEDLETM (the thinnest available aesthetic needle) could be recommended.

Figure 13 Patients with type 3 lines lack both structural support and collagen and require a combined approach. In the first
Boundaries of compartments. session, this will involve re-establishing the structural bone support and volume of the deep fat pads to reduce the
signs of age-related changes in the middle and lower face. In the second session, the remaining radial cheek lines will
be treated directly [Cotofana et al, 2018].

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 Table 7 Lower face indications

Indication Product / needle Volume Injection plane Technique Labiomandibular sulcus (Marionette Lines) and sunken corners of the mouth
or cannula size
Landmark deficiencies
Type 1 lines CPM-HA I / 27G needle 0.2 ml/ injection Supra-periosteal 2 small boluses injected in The marionette lines run from the oral commissure to the mandible and form the prejowl sulcus following the medial
(due to structural or 22-25G cannula point; 0.1 ml/bolus lateral cheek to enhance bone border of the depressor anguli oris muscle, which is where the platysma interdigitates. Sunken corners of the mouth
deficiencies) support over zygomatic arch represent the uppermost part of the marionette lines.
and along angle of
the mandible and
mandibular ramus Anatomical considerations
The marionette lines are influenced by a number of different aging-related changes in the lower face. The maxilla,
Type 1 lines CPM-HA V / 22-25G 1.0-1.5 ml/side; Deep medial For medial cheek volumizing mandible and the teeth provide support for the overlying tissues of the lower face, but changes in this skeletal support
(due to structural cannula 0.1 ml/thread cheek fat pad or product is injected in the fat pad with age result in descent of the overlying fat pads, and lines and folds appearing in areas where the muscles attach
deficiencies) Ristow’s space using a fanning technique and to the skin. This has been illustrated in a paper that examined perioral wrinkles before and after dentures were fitted
along post-jowl sulcus; combine in edentulous patients [Lupi et al, 2016]. The structural support provided by the dentures significantly improved the
with neurotoxin treatment appearance of the perioral lines including marionette lines without any other aesthetic treatments being performed.
of platysma
The marionette lines are also at the intersection of two different types of subcutaneous tissue arrangements. Lateral
to the marionette lines are the subcutaneous superior and inferior jowl fat compartments, whereas medial to the
Type 2 lines CPM-HA B / 30G 0.5-1.0 ml/ side Superficial reticular Blanching technique, multiple marionette lines there are multiple connections between the dermis, muscle and underlying soft tissues, which allow
(due to skin laxity) needle† CPM-HA S / depending on dermis punctures; combine with the dermis to move according to muscle function in this highly mobile area [Ghassemi et al, 2003]. At the top of this
invisible needle may be severity; 0.01-0.02 botulinum neurotoxin treatment intersection is the modiolus, which is where all the perioral muscles converge. It is continuous with the platysma
used in patients with ml/droplet of platysma which interdigitates with the depressor anguli oris (DAO) muscle and a portion of the orbicularis oris muscle. With
very thin skin or very skeletal volume loss, there is therefore a greater pull on the platysma and DAO, which ultimately influences the
superficial lines. position of the corner of the mouth [de Almeida et al, 2017].

Type 3 lines CPM-HA I / CPM-HA-V According to According to selected According to selected product
(due to structural and CPM-HA B /CPM- selected product product see above see above (combined with Product and injection technique
deficiencies and HA S see above neurotoxin treatment of As a result of the above anatomical considerations, experts agreed that marionette lines should only be treated after
skin laxity) platysma) volume loss of the maxilla and mandible have been addressed. For lines remaining after treatment of other areas the
selected product would depend on line severity. For superficial lines the experts recommended CPM-HA B up to
0.5 ml/side injected with an intradermal blanching technique (Table 8). For more severe lines, the consensus was for
Recommendations for radial cheek lines. CPM-HA I injected subdermally from the prejowl sulcus and advancing towards the top of the marionette line.
Level of consensus: Strong. †Majority agreement.
For sunken corners of the mouth, all experts agreed that this represents a tertiary area of injection. Authors agreed that
they would preferably use CPM-HA I, but CPM-HA V or CPM-HA B can also be used interchangeably depending on
availability of residual product that is left after all other deficits have been addressed. Injections of small boluses (0.1
Avoidance of complications ml) are made into the lateral corner of the lower vermilion border, upper vermilion border and then perpendicular to
The facial artery often runs on bone at the mandible in the antegonial notch, and working its way up more the lip to project the corners of the mouth (Figure 15).
superficially into the subcutaneous plane once it passes the oral commissure. Care must be taken when injecting.
Injectors should also know the location of the angular and infraorbital arteries. In case of severe elastosis and very
deep, scar-like wrinkles, ablative procedures might be performed in advance of the filler procedures.

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 Table 8

Indication Product / needle or Volume Injection plane Technique

cannula size

Marionette lines CPM-HA B 30G Up to 0.5 ml/ side; Superficial dermis Blanching technique, multiple
needle 0.01-0.02 ml/droplet punctures for superficial lines

CPM-HA I 27G 0.5 ml/side; 0.1 ml/ Subdermal Entry point at prejowl sulcus or
needle or 25 or 22G thread medially in the mentum and advancing
cannula towards oral commissure. Alternative
entry point is in medial chin.

Sunken corners CPM-HA I 27G 0.1 ml boluses; 0.05- Subdermal (CPM-HA Considered tertiary areas of injection
of mouth needle, (CPM-HA 0.2 ml/side I and CPM-HA V) or after all other deficits addressed. Use
V 27-30G needle intradermal (CPM- remaining product to inject lateral
or CPM-HA B 30G HA B) lower and upper vermilion border.
needle)

Recommendations for marionette lines and sunken corners of the mouth.

Level of consensus: Strong.

Figure 15 Chin
Marionette lines – injection technique.
Landmark deficiencies
Augmentation of the chin is a powerful way of improving facial harmony and treatments may be used to widen or
elongate the chin and thus alter facial shape [Wilson et al, 2018]. Patients presenting for chin enhancement generally
Avoidance of complications fall into two categories [Lee, 2013]. The first group consists mainly of younger patients who have either a genetically
The facial artery generally runs about 1 cm lateral to the oral commissure and is connected to the modiolus by a under-formed chin or who are looking to improve their appearance by making their face shape more feminine or
muscular band of the buccinato rmuscle [Thomaidis, 2014]. masculine. The second group comprises older patients whose chin shape may have changed as a result of bone
resorption and/or soft tissue atrophy. There are also ethnic preferences, for example, Asian patients often request a
chin treatment that creates a more heart-shaped face.

Anatomical considerations
In Western cultures, the ideal width of the female chin is approximately the same width as the intercanthal distance.
In men the chin is wider and approximately the width of the mouth. Care must be taken not to masculinize a female
face by making the chin too wide. The ascending mental artery runs in the subdermal plane in a paramedian vertical
direction, whereas the mental artery runs horizontally in the supraperiosteal plane after emerging from its foramen.
The mental artery connects via multiple periosteal branches to the submandibular artery, which are frequently found
in the deep plane deep to mentalis muscle.

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 Product and injection technique Chin projection
To obtain the ideal chin projection in relation to the vermillion [Wilson et al, 2018], injections are placed in the
Chin elongation pogonion area (Figure 16). The preferred product is CPM-HA V (1-2 ml), injected with either a blunt cannula (22-25G)
Elongating the chin can be effective for balancing facial proportions [Wilson et al, 2018] and involves injection of the and epiperiosteal (deep fat) injection, or needle (27-30G) and tower technique (Table 9). Before and after photos
menton (Figure 16). The preferred product is CPM-HA I because of its high elasticity and projection properties (Table of a patient treated for chin projection are shown in Figure 18. Patients with a strong mentalis muscle may require
9). A total amount of 1-2 ml is injected with either a blunt cannula (22G) or needle (27-30G) as multiple boluses in 1-2 botulinum toxin to relax the muscle before beginning chin augmentation, ideally 10-14 days in advance. In Asian
lines on the periosteum along the inferior border of the mandible until the required chin length and width is achieved. patients with a strong mentalis and a thick skin a two-step injection approach may be necessary injecting up to 2 ml
Before and after photos of a patient treated for chin elongation are shown in Figure 17. of the product in each session. In patients requiring both elongation and projection, elongation should be performed
first followed by projection.

Mentum: 1–2 lines

punctual augmentation implementing
width and length of the chin
Pogonium: periostal punctual and
augmentation
1–2 ml
Pre jowl sulcus: digital guided
musoca based tower technique
0,5–1 ml
Submental crease (if necessary):
digital guided musoca based
tower technique

Figure 16
Injection points for chin elongation and chin projection.

Figure 18
Before and after photos of a patient treated for chin projection.

Table 9

Indication Product / needle or Volume Injection plane Technique

cannula size
Chin elongation CPM-HA I / 22-25G 1-2 ml; 0.1 ml/bolus Periosteum Inject multiple boluses in 1-2
and width cannula or 27 needle lines along inferior border of
mandible

Chin projection CPM-HA V / 22-25G 1-2 ml; 0.1 ml/bolus Epiperiosteal Inject pogonion using multi-
Figure 17 cannula or 27-30G (cannula), level technique (Sandwich
Before and after photos of a patient treated for chin elongation. needle periosteum upwards technique with the cannula
(needle) or Tower technique with the
needle)

Recommendations for chin augmentation.

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 Avoidance of complications
Due to anastomoses in chin arterial circulation (mental artery, inferior labial artery, labiomental artery), use of a blunt
tip cannula is recommended with slow injection of multiple boluses to minimize risks.

Jawline

Chin and jawline treatments are generally performed together (with the chin treated first) as the two areas must be
blended to ensure smooth contours.

Landmark deficiencies
With age, bone resorption, soft tissue descent and skin laxity result in a loss of definition of the jawline with jowl
formation, irregular contours and blunting of the mandibular angle [Suwanchinda et al, 2018].

Anatomical considerations
Bone resorption results in decreases in mandibular body height, ramus height and mandibular body length,
all of which cause the mandibular angle to move medially along with the soft tissues that are attached to bone
[Suwanchinda et al, 2018]. Jawline treatment should therefore focus on restoring age-related bone loss and
submuscular aponeurotic system (SMAS) tension. Injections in the jowl fat should be avoided as they can accentuate
the boundary between the different types of subcutaneous arrangements that form the sulcus [Suwanchinda et al,
2018] and thereby lead to a more masculine appearing chin.

Figure 19
Product and injection technique Injection points for jawline rejuvenation. Schematics © Dr. Jani van Loghem
For defining the jawline, the consensus was for injection of CPM-HA I. Two insertion points are recommended (Table
10). The first is at the mandibular angle with injections in the subdermal plane and directed towards the zygomatic
arch, with a supraperiosteal bolus at the mandibular angle itself (both would be performed with a 22G stiff cannula)
(Figure 19). The second is at the prejowl sulcus, medial to the vessels with injections performed subdermally towards A B
the mandibular angle (the vessels can be crossed as they are deep and the cannula subdermal). The direction is then
changed and injections performed towards the chin, using subdermal linear threading and placing a small bolus on
the bone at the origin of the mandibular ligament. No product should be injected into the jowl fat. Before and after
photos of a patient treated for the jawline are shown in Figure 20.

Figure 20
A: Before and B: after photos of a patient treated for jawline rejuvenation. Courtesy dr. Jani van Loghem, MD

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 Table 10 With age, it is not necessarily lip volume that is lost, but instead a repositioning of the existing volume due to
increasing lip length as a result of skeletal changes [Ramault et al, 2019]. These patients do not requiring volumizing
Indication Product / needle or Volume Injection plane Technique but architectural restructuring and contouring to re-establish shape, which can be achieved by injecting a matrix of
cannula size filler threads.

Jawline CPM-HA I 22-25G 2 ml/side; Subcutaneous Insertion points at Emphasis should be placed on tailoring treatment with consideration given to landmarks such as the medial tubercle
cannula or 0.1 ml/bolus jowl (or prejowl sulcus) and recreation of the J-shape. Treatments should also be performed with appropriate ethnic considerations. There
27G needle and mandibular angle are large differences in lip proportions between African American, Asian and Caucasian ethnic groups, for example
in relation to vermilion height and lip protrusion [Wong et al, 2010; de Freitas et al, 2010; Wen et al, 2015]. The
Recommendations for marionette lines and sunken corners of the mouth. vermilion border is not a primary concern in south-east Asian patients, but is popular in middle-eastern patients.
Level of consensus: Strong

Product and injection technique

Avoidance of complications Lip contouring

Both the facial and the external carotid arteries run deep in the jawline area; the facial artery runs over the periosteum Prior to injection, patients should be assessed for both lip contour (vermilion border) and lip volume as one has
just anterior to the masseter muscle and the external carotid artery runs deep to the mandible, dorsal to the ramus. an influence on the other. For restoring upper lip contour and a J-shape on lateral view, all experts recommended
If injecting at the chin or mandibular angle, injections can be performed supraperiosteally, but injections at points in CPM-HA LC (Table 11). The high cohesivity and low elasticity of this product allow the lips to be contoured without
between these landmarks should therefore be subcutaneous. Care must also be taken to avoid the parotid gland, facial creating too much outward projection. It is injected as threads of <0.05 ml (needle) or 0.1-0.2 ml/side (cannula) with
veins and stenson’s duct, which are located sub-SMAS and lie over the masseter muscle. an entry point just lateral to the oral commissure. Experts were divided on whether a 25G cannula or 30G needle
should be used. While needles may be used for lateral aspects, caution should be used around the midline and the tip
of the needle kept in view. Figure 21 shows before and after images of a patient treated with lip contouring.
Lip contouring, volumizing and perioral lines

Landmark deficiencies
Lack of lip definition may be congenital or associated with aging. An optimal lip contour comprises a well-defined A B
upper and lower vermilion border, cupids bow, and a J-shaped curve to the upper lip [Ghannam et al, 2019]. In
younger patients, the vermilion border, especially in the upper lip, is usually well defined, but definition is lost with
age as a consequence of elongation of the upper lip and photo damage [Wollina, 2013]. A lack of definition along the
vermilion border can accentuate the appearance of perioral lines (smokers lines) [Hotta, 2016].

In addition to lip contouring, enhancement of lip volume is one of the most frequently demanded aesthetic
indications, particularly in younger patients [Sarnoff & Gotkin, 2012]. Other popular indications in this age group
include lip hydration and lip projection. Most patients prefer a natural aesthetic improvement, but some may request
a more visible, less natural lip augmentation. Physicians should not be pressured into performing a procedure
they believe is unaesthetically pleasing and should try to convince patients that overfilled lips are not a desirable
aesthetic result.

Anatomical considerations
The lips are very well vascularized and as a consequence injected product is never far from a vessel. In a recent
anatomical study, a range of injection techniques commonly used to treat the lips with either a needle or cannula
were examined for subsequent placement of product. The results revealed that injected material was frequently Figure 21
placed in close proximity to the labial arteries, thus representing a high risk for intra-arterial events [Ghannam et al, A: Before and B: after photos of lip contouring. Patient also received lip volumizing.
2019]. The vasculature of the lips is also highly variable, and the course of the superior and inferior labial arteries Courtesy Dr. Jani van Loghem, MD.
within the upper and lower lips is not always submucosal (between the oral mucosa and the orbicularis oris muscle)
[Cotofana et al, 2017b]. A study of 193 cadavers reported labial artery position as submucosal in 78.1% of cases,
intramuscular in 17.5% of cases, and subcutaneous in 2.1% of cases [Cotofana et al, 2017b]. The course of the arteries
also switched between planes at least once in around a third of the cadavers, with the greatest variability observed in
the midline location. As a result, injections should be performed in the subdermal plane in the lateral aspect of the
lips and care should be taken when augmenting around the midline.

206 chapter 10 207

 Lip volumizing Table 11
When classified according to the Merz Aesthetics lip fullness scale [Carruthers et al, 2008], experts would volumize
lips of grades 0 to 3, and with exception to grade 4. For volumizing the vermilion, CPM-HA LS is preferred (Table Indication Product / needle or Volume Injection plane Technique
11). For a natural look, no more than 0.5-1.0 ml should be injected per side. Product should be injected with a cannula size
needle (30G) or cannula (25G, 38 or 40 mm) as a series of linear threads and not as a bolus [Pavicic et al, 2019]. For
restructuring the older lip, CPM-HA LS is preferred for submucosal projection to correct bone resorption, but CPM- Lip contouring CPM-HA LC / 25G <0.05 ml threads Superficial dermis Injection along vermilion
HA LC may also be used at a volume of 0.3-0.5 ml/side. Restructuring of the body of the lip should be performed cannula or 30G needle† (needle), 0.1-0.2 ml/side border. Entry point for the
alongside contouring the vermilion border. Figure 22 shows before and after images of a patient treated with (cannula) cannula just lateral to the
lip volumizing. oral commissure

Lip Volumizing

A B Volumizing vermilion CPM-HA LS or CPM-HA I 0.5-1.0 ml/ side of upper Subdermal Inject as a series of linear
depending on the amount or lower lip; 0.05-0.1 ml/ threads (not bolus).
needed (CPM-HA LC retrograde thread
is an option for minor
improvements)
25G cannula

Restructuring CPM-HA LS or CPM-HA I 0.3-0.5 ml/ side of upper CPM-HA I preferred for
(CPM-HA LC is an option) or lower lip; 0.05-0.1 ml/ subcutaneous placement to
depending on the amount thread give anterior lip projection
needed 25G cannula

Perioral lines CPM-HA LC 30G needle <0.01/point; 0.5-1.0 ml Superficial dermis Blanching technique,
total multiple punctures

Figure 22 Philtral columns CPM-HA LS or CPM-HA 0.05-0.1 ml/side in a Intradermal Retrograde linear threads
A: Before and B: after photos of lip volumizing. Courtesy Dr. Jani van Loghem, MD. B 30G needle retrograde linear thread from the base of the philtral
column at the vermilion
border

Recommendations for the lips.

Perioral lines Level of consensus: Strong. † Experts were divided on whether a cannula
Perioral lines can be improved by first contouring the vermilion border as above. Prior to treatment it should also or 30G needle should be used for the upper lip vermilion border.
be determined whether the lines are associated with concomitant elastosis, in which case a resurfacing treatment
is required. If there is no elastosis, the experts recommended injection of CPM-HA B with a 30G needle using a
blanching technique and injecting <0.01 per point along the static perioral lines (Table 11). CPM-HA S could also be
used with the “invisible” needle, or both CPM-HA B and CPM-HA S in combination using a sandwich technique. If Avoidance of complications
elastosis is also present, the recommendation was to wait at least 2 weeks before performing resurfacing techniques The superior and inferior labial arteries are at risk for embolization. The safest position for the injection of product
with energy-based devices [Fabi et al, 2016]. when volumizing the lip is in the subcutaneous plane of the lateral upper and lower lip, around the midline these
arteries are more frequently found in superficial positions.
To define the philtral columns and improve the lateral view of the lips, the recommendation was for intradermal
(dermal/muscle interface)/subdermal injection of <0.1 ml CPM-HA B or CPM-HA LC with a needle (Table 11).

208 chapter 10 209

 Skin revitalization Table 12

Landmark deficiencies
Endogenous HA is important for providing skin hydration and skin turgor, and when levels are reduced can lead to Indication Product / needle or Volume Injection plane Technique
lax and dull-looking skin [Bukhari et al, 2018]. Skin revitalization with microinjections of HA is of benefit in younger cannula size
patients who notice loss of elasticity, dry and tired looking skin despite a daily skin care routine, but who do not
need treatment with volumizing fillers. In older patients, skin revitalization can be combined with all rejuvenation Skin-revitalization CPM-HA S / 32G 4 0.02-0.05 ml/bolus; 1 ml/ Immediate Multiple punctures over 3
procedures to improve skin quality and skin elasticity. mm needle or 30G side (face); 0.5 ml/back subdermis sessions 1 month apart with
needle of the hand; 1 ml/side of maintenance sessions every 6
the hand; 1 ml/session Immediate months
Anatomical considerations CPM-HA R / 32G 4 perioral; 1 ml/session neck; subdermis
HA products formulated for skin revitalization can be injected over large treatment areas of the face, neck, mm needle or 30G 2–3 ml per session for the Injections spaced 1 cm apart.
décolletage and hands to increase skin hydration, skin surface smoothness, skin elasticity and skin glow. In addition, needle decollete Treatment delivered in 3
the multiple small depots of HA activate fibroblasts promoting new collagen and elastin formation [Wang et al, 2007; sessions 1 month apart and
França Wanick et al, 2016]. Injections are not targeting specific wrinkles, but treating the face as a whole to improve 0.02 ml per droplet thereafter by maintenance
skin quality and therefore are not recommended to be injected using the blanching technique. sessions every 8-12 months

Product and injection technique Recommendations for skin revitalization.

Using CPM-HA S the injection protocol typically takes place over three sessions each spaced 1 month apart, followed Level of consensus:
by a maintenance phase of one session approximately every 6 months (Table 12). Injections are performed with a 32G
short needle in the mid to deep dermis or in the immediate subdermis. In addition to improving skin quality, potential
other indications for this technique include reducing pore size [Qian et al, 2018] and improving melasma.
Avoidance of complications
CPM-HA R, the newest addition to the CPM-HA range, is a slightly crosslinked HA (20 mg/ml) with added glycerol No subcutaneous injections should be performed with the needle because of proximity to vessels, especially in the
(17.5 mg/ml) that has been specifically formulated to improve skin hydration, elasticity, firmness and glow [Hertz- area around the nasolabial fold. Avoid large boluses with the blanching technique as the papules might be visible and
Kleptow et al, 2019]. The addition of glycerol as a humectant provides deep and immediate hydration [Korponyai et palpable for several days.
al, 2017]. In the BELOVE 1 study, 25 patients received injections in the lower cheek area at 4-week intervals and were
observed over a 36-week period [Hertz-Kleptow et al, 2019]. Patients noticed improved skin hydration after only 1
week of treatment, which continued to improve up to week 36. They also noted a gradual increase in glow (seen as a
reduction in redness) over 36 weeks.

CPM-HA R should be injected with a 32 G short needle or the so-called invisible needle in the immediate subdermis.
The injection amount is approximately 0.02 ml per droplet with injections spaced 1 cm apart. In the BELOVE 1 study,
patients each received 20 micropuncture treatments of 50 µL CPM-HA R into the lower cheek in three sessions
spaced 1 month apart followed by a maintenance session 8-12 months later. However, treatment sessions should
be individualized according to patients’ skin quality (Table 12). A topical anesthetic should be applied in advance in
sensitive patients.

210 chapter 10 211

 Table: Upper Face

Region Indication Most Location/ Product Needle/ Injection Amount of Comments Con- Region Indication Most Location/ Product Needle/ Injection Amount of Comments Con-
probable plane of cannula techni- product sensus probable plane of cannula techni- product sensus
location injection que location injection que
of artery of artery
Posterior Intrafascial Subdermal (1) CPM- Stiff Linear 0.5-1.0 ml/ Temporal crest Strong
Upper Face
temporal and supra- HA V cannula threading side, higher entry point,
Forehead Lateral Subcuta- Suprape- (1) CPM- Stiff Linear 0.5-1 Lateral entry compart- periosteal (2) CPM- ≥25G volumes from frontal
frontal neous riosteal HA-V / cannula threading ml/side points 1.5-2.0 cm ment HA I may be periosteum
hollowing plane CPM-HA I ≥25G 0.025- above orbital rim required through temporal
(2) CPM- 0.04 ml/ at the temporal if volume crest into the
HA B thread crest; optional loss seve- interfascial
additional entry re; 0.05-0.1 space. Multiple
point higher to- ml/thread passes injecting
wards hairline. small amounts.
With lateral entry Zygomatic arch
points inject entry point,
in a direction staying strictly
perpendicular to hypodermally,
arteries multiple passes
hairline and
Central Subcuta- Suprape- (1) CPM- Stiff (1) Linear 0.5 ml/side Central entry upwards injecting
frontal neous riosteal HA-V / cannula threading 0.025- point just above tiny threads (only
hollowing plane CPM-HA I 22G (2) Small 0.04 ml/ frontal concavity CPM-HA V)
(2) CPM- boluses thread below hairline
HA B Posterior Subdermal CPM-HA B Stiff Linear 0.5-1.0 ml/ Temporal crest Strong
temples cannula threading side; 0.05 entry point.
Temple Upper Intrafascial (1) Subder- (1) CPM- (1) Stiff (1) Linear 0.1 ml/bo- Strong visible 22G ml/thread Multiple passes
hollowing anterior and supra- mal HA V cannula threading lus, 0.5-1.0 temporal injecting small
temporal periosteal (2) Supra- (2) CPM- ≥25G (2) Bolus ml/side blood amounts. Zygo-
compart- periosteal HA B (2) 27G <0.3 ml vessels matic arch entry
ment needle and very point, staying
thin skin strictly hypoder-
Lower Intrafascial Subdermal (1) CPM- (1) Stiff Linear Strong mally, multiple
temporal and supra- HA V cannula threading passes hairline
compart- periosteal (2) CPM- ≥25G and upwards
ment HA I (2) 30G injecting tiny
needle threads
Periorbital Supraor- Deep to CPM-HA B Stiff 0.3-0.5 ml/ Preinsertion Strong
Continued on next page bital orbicula- cannula side (0.025 point made with
hollowing ris oculi 25G ml/droplet) 23G needle on
muscle in the lateral supe-
preseptal rior orbital rim.
fat and CPM-HA I may
above be used for seve-
levator re hollowing and
aponeu- CPM-HA S for
rosis mild hollowing.
Undertreatment
advised

212 chapter 10 213

 Table: Midface

Region Indication Most Location/ Product Need- Injection Amount of Comments Con- Region Indication Most Location/ Product Need- Injection Amount of Comment Con-
probable plane of le/can- techni- product sensus probable plane of le/can- techni- produc sensus
location injection nula que location injection nula que
of artery of artery
Lateral Pre- Sub- Subdermal CPM-HA V Stiff Linear 0.1-0.5 ml/ To create pre- Strong
Midface
midface auricular cutanous cannula threading, side; 0.05- auricular
Infraorbi- Stage 1 Periosteal CPM-HA I or Stiff 0.5 ml/ Injection in SOOF Strong hollowing 22-25G retro- 0.1 ml/ hollowing a
tal hollo- (IOH): ZCL at the origin CPM-V cannula side; 0.05- below zygomatic grade thread vectoring
wing and ZRL of the ZRL 25G 0.1 ml/ cutaneous and fanning approach is used
ligaments and ZCL bolus zygomatic retai- technique to augment and
ning ligaments to lift across the
reposition them zygoma taking
more horizontally care to create a
more ovoid
Stage 2 Periosteal (1) CPM- Can- 0.2-0.5 Target palpe- Strong hollowing in wo-
(IOH): pal- HA B nula 23- ml/side; bromalar groove men and sharper
pebroma- (2) CPM-HA 25G 0.025- inferior to orbi- *Re- hollowing in men.
lar groove I or CPM-HA 0.05 ml/ cularis retaining com-
Radial
V* thread ligament. Inser- mended cheek lines
tion point lateral by 3
to orbicularis experts Type 1 Suprape- CPM-HA I Cannu- 0.2 ml/ 2 small boluses Strong
oculi muscle skin (structural riosteal la 22- injection injected in lateral
insertion. deficien- 25G or point; 0.1 cheek to enhance
Or using same cies) needle ml/bolus bone support
insertion point as 27G over zygomatic
for tear trough, arch and along
place small angle of the
amount of pro- mandible and
duct below lateral mandibular ramus
orbital thickening Deep CPM-HA V Cannu- 1.0-1.5 ml/ For medial cheek Strong
medial la 22- side; 0.1 ml/ volumizing pro-
Stage 3 Subcuta- (1) Supra- (1) CPM- Stiff 0.1-0.5 Injections are Strong cheek fat 25G thread duct is injected
(IOH): tear neous periosteal HA B cannula ml/side; placed deep on pad or in the fat pad
trough (CPM-HA (2) CPM- 25G 0.025- the periosteum *Re- Ristow’s using a fanning
B) HA S 0.05 ml/ between the ORL com- space technique and
(2) Sub- thread and zygomatic mended along post-jowl
cutaneous Max 0.1 cutaneous liga- by 3 sulcus; combine
(CPM-HA ml/side of ment taking care experts with neurotoxin
S* CPM-HA S to stay below treatment
if injected malar septum
subcuta- and only inject Type 2 Superficial CPM-HA B Needle 0.5-2.0 Blanching Majority
neously small amounts lines (skin reticular CPM-HA S 30G ml/ side technique, mul- agree-
laxity) dermis and invisible depending tiple punctures; ment
needle may on severity; combine with
Continued on next page
be used in 0.01-0.02 neurotoxin treat-
patients with ml/droplet ment
very thin
skin or very
superficial
lines

214 chapter 10 215

 Table: Lower Face

Region Indication Most Location/ Product Needle/ Injection Amount of Comments Con- Region Indication Most Location/ Product Needle/ Injection Amount of Comments Con-
probable plane of cannula techni- product sensus probable plane of cannula techni- product sensus
location injection que location injection que
of artery of artery
Perioral
Lower Face

Marionette (1) Superfi- (1) CPM- (1) Need- (1) Up to 0.5 (1) Blanching Strong Lips Sub- Subder- CPM-HA Stiff Linear <0.05 ml Injection along Strong
lines cial dermis HA B le 30G ml/ side; technique, multi- contouring mucosal mal/intra- LC cannula threading threads vermilion
(2) Subder- (2) CPM- (2) Need- 0.01-0.02 ple punctures for dermal 25G/ (needle), border. Entry
mal HA I le 27G or ml/droplet superficial lines needle 0.1-0.2 point for the
22-25G (2) 0.5 ml/ (2) Entry point at 30G† ml/side cannula just
cannula side; 0.1 ml/ prejowl sulcus (cannula) lateral to the oral
thread and advancing commissure
towards oral
commissure. Lips Sub- Subdermal (1) CPM- (1) Stiff (1) Linear 0.5-1.0 Strong
Alternative entry volumizing mucosal HA LS cannula threading ml/ side of
point is in medial (2) CPM- 25G (2) Per- upper or
chin? HA I (2) pendicu- lower lip;
CPM- Needle lar linear 0.05-
Jawline HA LC 27-30G threading 0.1 ml/
Mandibular Subcuta- (1) Subder- CPM-HA (1) Stiff Small 2 ml/side; Insertion points is option retrograde
angle con- neous mal V or CPM- cannula boluses 0.1 ml/ at jowl (or prejowl for minor thread
touring (2) Supra- HA I ≥25G bolus sulcus) and man- improve-
periosteal (2) Need- dibular angle ments
(intamus- le 27 or
cular) 30G Philtral Subcuta- Intrader- (1) CPM- Needle Linear 0.05-0.1 Retrograde linear Strong
contouring neous mal HA LC 30G threading ml/side in a threads from
Chin pro- Subcuta- Suprape- (1) CPM- (1) Small 1-2 ml; 0.1 Inject multiple (2) CPM- retrogra- the base of the
longation & neous riosteal + HA I Cannula boluses ml/bolus boluses in 1-2 HA LS de linear philtral column
"pointing" intradermal (2) CPM- 22-25G lines along thread at the vermilion
(inferior) HA V (2) Need- inferior border of border
le 27 or mandible Lip restruc- (1) CPM- 0.3-0.5 CPM-HA I Strong
30G turing HA LS ml/ side of preferred for
(2) CPM- upper or submucosal
Chin Subcuta- Epipe- CPM-HA V (1) Stiff Small 1-2 ml; 0.1 Inject pogonion HA I (CPM- lower lip; placement to
projection neous riosteam cannula boluses ml/bolus using multi- HA LC is 0.05-0.1 give anterior lip
(anterior) (cannula), ≥25G level technique an option) ml/bolus projection
periosteum (2) Need- (Sandwich depending
upwards le 27 or technique with on the
(needle) 30G the cannula or amount
Tower needed
technique with Perioral Superficial CPM-HA Needle Blan- <0.01/
the needle) lines dermis LC 30G ching point; 0.5-
Between Suprape- Subdermal CPM-HA I Stiff tech- 1.0 ml total
chin and riosteal cannula nique,
mandibular 22G multiple
angle punctu-
res
Continued on next page † Experts were divided on whether a cannula or 30G needle should be used for the upper lip vermilion border.

216 chapter 10 217

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Use of hyaluronic acid gel for upper eyelid filling and Reconstruction: From Anatomy to Surgery, Lips and Chin.
contouring. Ophthalmic Plast Reconstr Surg. 2009 Nov- 2014; p. 265.
Dec;25(6):440-4. 40. Tran C, Carraux P, Micheels P, Kaya G, Salomon D. In vivo
29. Pavicic T, Webb KL, Frank K, Gotkin RH, Tamura B, bio-integration of three hyaluronic acid fillers in human
Cotofana S. Arterial wall penetration forces in needles skin: a histological study. Dermatology. 2014;228(1):47-
versus cannulas. Plast Reconstr Surg. 2019a;143(3):504e- 54.
512e. 41. Wang F, Garza LA, Kang S, et al. In vivo stimulation of
30. Pavicic T, Mohmand HM, Yankova M, Schenck TL, Frank de novo collagen production caused by cross-linked
K, Freytag DL, Green JB, Hamade H, Cassuto D, Cotofana hyaluronic acid dermal filler injections in photodamaged
S. Influence of needle size and injection angle on the human skin. Arch Dermatol. 2007;143:155-163.
distribution pattern of facial soft tissue fillers. J Cosmet 42. Wen YF, Wong HM, Lin R, Yin G, McGrath C. Inter-
Dermatol. 2019b Jul 8. doi: 10.1111/jocd.13066. [Epub Ethnic/Racial Facial Variations: A Systematic Review and
ahead of print] Bayesian Meta-Analysis of Photogrammetric Studies. PloS
31. Qian W, Zhang YK, Hou Y, Lyu W, Cao Q, Li YQ, Fan JF. J One. 2015;10(8):e0134525.
Cosmet Dermatol. 2018 Aug;17(4):596-599. 43. Wilson M, Jones I, Butterwick K, Fabi SG. The role of
32. Ramaut L, Tonnard P, Verpaele A, Verstraete K, Blondeel nonsurgical chin augmentation in full face rejuvenation: A
P. Aging of the upper lip: part I: a retrospective analysis Review and Our Experience. Derm Surg 2018
of metric changes in soft tissue on magnetic resonance 44. Wollina U. Perioral rejuvenation: restoration of
imaging. Plast Reconstr Surg. 2019;143(2):440-446. attractiveness in aging females by minimally invasive
33. Sarnoff DS, Gotkin RH. Six steps to the “perfect” lip. J procedures. Clin Interv Aging. 2013;8:1149–1155.
Drugs Dermatol. 2012 Sep;11(9):1081-8. 45. van Loghem JA, Humzah D, Kerscher M. Cannula
34. Schenck TL, Koban KC, Schlattau A, Frank K, Sykes JM, Versus Sharp Needle for Placement of Soft Tissue
Targosinski S, Erlbacher K, Cotofana S. The functional Fillers: An Observational Cadaver Study. Aesthet Surg J.
anatomy of the superficial fat compartments of the 2017;38(1):73-88.
face: a detailed imaging study. Plast Reconstr Surg.
2018;141(6):1351-1359.

220 chapter 10 221

 General Discussion

222 general discussion 223

 general discussion
In Chapter 1, the General Introduction of this thesis, the official status in The Netherlands of the new medical profile especially with a needle or cannula in a static position, avoidance of high pressure injections, and selection of the
specialty of Aesthetic Medicine. The appearance of new treatment modalities as well as the advancement of filler anatomical layer where there is the least risk of intra-arterial injection.5 Even with these safety precautions, there is
indications, products and techniques have been developing at a very fast pace over the past few decades. As the never a guarantee of 100% safety during filler treatments. Therefor physicians should have a healthy worry when
most sought after and important rejuvenation modality, injectables, both fillers and botulinum toxins, have become treating their patients and be conservative. There is no such thing as a “safe zone” in the face. We can merely speak
the products of choice for most aesthetic physicians and play a central role in most aesthetic clinics around the about high-risk and low-risk areas. The same can be applied to injection techniques and instruments.
world.1 With limited available clinical research to support existing (often off-label) clinical practice, a guide to help
minimize complication risks and optimize patient safety would be of great value to treating physicians worldwide. In Chapter 5, we retrospectively studied the use of CaHA in three areas of the upper third of the face: frontal
Product-related complications are becoming less of a risk over time with improvements in quality of filler products, region, temporal hollows and lateral eyebrow. As these indications are normally treated with hyaluronic acid (HA)
and especially as permanent fillers are generally rejected by both physicians and patients. Most adverse events products, we sought to investigate the safety, efficacy and complication rates after injection of CaHA to the upper
such as bruising and swelling are mild and resolve without any sequelae. Of the serious adverse events, granuloma third of the face using a variety of different techniques. A total of 115 treatments performed over the course of 1
formation is a product-related late inflammatory complication, while necrosis and blindness are the two most serious year in our private practice were studied. The standard dilution of CaHA with 16.7% lidocaine and non-traumatic
complications that can be caused by technical errors.2 cannulas were the most frequently used and were effective and well-tolerated for indications in the upper third of the
face. No serious complications were recorded.6 Even though 70 patients were treated with CaHA during one year,
Chapter 2 focused on Calcium Hydroxylapatite (CaHA), a biostimulatory soft tissue filler marketed under the name approximately four times that number was treated with HA fillers in the upper third of the face in that period. So while
Radiesse®. As this filler is associated with the lowest risk of product-related complications among all filler substances, CaHA has a place in the upper third of the face, the golden standard still remains to be HA in our practice.
it is worthwhile examining ways in which it can be used as part of a pan-facial approach.3 CaHA procedures have
evolved over the last 16 years in many ways, in parallel with new insights into anatomy and the aging process. In Chapter 6 looked at how to reduce one of the most prevalent side effects of aesthetic injectable procedures: pain
addition, a better understanding of the mechanism of action of this established product has led to CaHA becoming a perception. As Dr. Arthur Swift so eloquently states in his keynote lectures: “If you bruise them, you lose them and if
very versatile filler that can be used for many different facial indications, with the caveat that safe injection techniques you pain them, you won’t retain them”. Using a visual analogue score, we measured pain perception on both sides
and instruments are used. A general protocol for a global facial rejuvenation strategy based on age-related anatomical of the face and randomized starting treatment to the right side or the left side. Even after correction for left- or right-
changes is presented for CaHA with both needles and cannulas.1 An important issue, however, is the skillset of handedness, we observed that the left side was more painful for the patient. Interestingly, treatments that started on
individuals performing the procedures. Of particular concern are non-physician injectors who may also have a the left side of the face resulted in less overall pain of the treatment.7 These findings have led to a general change
limited knowledge of facial anatomy and inadequate training. Especially the fact that CaHA poses the lowest risk of in our practice, where injections are now generally started on the left side of the face. Feedback from numerous
granuloma formation among all filler substances, makes this product very interesting. It’s non-reversibility does pose a colleagues around the world suggests that they too have changed to starting injections on the left side of their patients.
risk however, that is not associated with HA fillers as those can be reversed with hyaluronidase.
Chapter 7 looked at how different aesthetic intervention modalities such as cohesive polydensified matrix hyaluronic
Chapter 3 compared the use of two popular instruments for periosteal injection of filler products: sharp needles acid (CPM-HA), CaHA, incobotulinumtoxinA, micro-focused ultrasound with visualization (MFU-V) and other
versus blunt tipped cannulas. In a split-face observational cadaver study in which five common facial indications were modalities can be combined for the prevention of facial aging, and restoration and beautification of face and body
studied, cannulas were associated with lower risk and higher anatomical precision. We learned that even though indications. This was based on the outcomes of an advisory board meeting with experts from around the world
the needle may be in contact with the periosteum on injection, an intra-arterial injection is still possible due to the who convened to present and discuss evidence-based and best practice approaches to combining treatment
beveled shape of the needle tip. Precision was defined as predictability of the anatomical layer for the placement of modalities. When multiple treatments are required in one area, there was strong consensus that if undertaken on
filler products. Due to the perpendicular angle of the needle to the bone, back flow resulted in multilevel deposition the same day, incobotulinumtoxinA, CPM-HA, and/or CaHA may be performed in any sequence. When MFU-V
of filler products to more superficial anatomical layers. In contrast, the oblique angle of cannula placement resulted is one of the procedures, this should be performed before the filler or incobotulinumtoxinA. In the upper face,
in filler deposition at the level of the preperiosteum with significantly less back flow to more superficial anatomical incobotulinumtoxinA is recommended for muscle control; for patients presenting with volume depletion of the
layers. As competence with a blunt-tipped cannula has a longer learning curve than a needle, physician education forehead and temples, the recommendation is to start with an HA. In the midface, CPM-HA and/or CaHA are
is very important. Intra-arterial injection of filler products is associated with the most devastating complications recommended for volume loss in the cheek without laxity; however, in the presence of laxity, the consensus
including blindness and tissue necrosis, arguing in favor of cannula use.4 recommends starting with MFU-V followed by CPM-HA and/or CaHA. In the lower face, combination treatment
using incobotulinumtoxinA to relax any areas with a downward pull, and CPM-HA and/or CaHA to create structure
In Chapter 4, the reliability of aspiration as a safety test for the avoidance of intra-arterial injection was studied. This and volume, is recommended. For the neck, incobotulinumtoxinA is recommended as a first-line treatment, followed
in vitro experimental procedure involved injecting different brands of fillers with various sharp needle sizes using by MFU-V and low-viscosity CPM-HA and/or diluted CaHA as second- and third-line treatments, respectively, to
both colored Ringer’s lactate as well as anti-coagulated blood pressurized to an arterial pressure of 150 mm Hg. The stimulate neocollagenesis and improve skin texture.8 To offer patients the best possible outcomes, we should look at
reliability of aspiration was found to be dependent on several factors including product rheology (gel characteristics the face as a whole and at different tissue depths to determine the most appropriate treatment approach. Recognizing
such as viscosity, elasticity, cohesively and plasticity), needle gauge (diameter, thickness), needle length, and time of that more than one procedure will be required to correct all the issues, injectables and other modalities such as
aspiration. Based on these findings it can be concluded that aspiration is unreliable as a safety test before injecting energy-based devices can be combined for optimal results. Even though it is evident that patient satisfaction is very
(gel-based) fillers. Although it remains a highly-sensitive test when blood is drawn up into the syringe, it has low high on combining different treatment modalities, combinations may raise questions on risk factors because of
specificity as a negative test result may be false-negative. As a result, we advise additional safety precautions should combining different products. Much more research is necessary to investigate safe combinations and long term repeat
be taken such as the use of large gauge needles or blunt-tipped cannulas, avoidance of high volume bolus injections, treatments using different products.

224 general discussion 225

 general discussion impact of this thesis and future developments
Chapter 8 provides the aesthetic practitioner with practical recommendations concerning the diagnosis of common Moving forward, much more research will be necessary to define the new medical field of aesthetic medicine and
complications arising after HA filler treatment, as well as recommendations for their management. For practical to further reducing the risk of complications and improve patient safety during facial filler treatments. A number of
purposes, the differential diagnoses are grouped according to the principal clinical finding, and the therapeutic players will have key roles in this process. The pharmacological companies provide the filler products and instruments
approaches outlined in the step-wise treatment algorithms are based on published expert opinions, as well as the that physicians use to inject their patients. Anatomists are providing new insights into the aging process and injection
clinical experience of the authors. Skin discoloration, edema, nodules, infections and vascular compromise are danger zones that will determine new technical approaches. Perhaps most importantly, the aesthetic physicians have
discussed in detail, including possible differential diagnosis, and clear recommendations are presented for the to lay the scientific foundations of this new medical specialty. This will require careful discussion to determine the
prevention and treatment of these complications. These guidelines are not intended to be complete or exhaustive, but needs of their patients, combined with innovation and creativity to develop new ideas, approaches and techniques
may prove informative for aesthetic clinicians who are responsible for treating patients with HA fillers. Their aim is to that address these needs. This will undoubtedly result in a shift from standard protocols towards personalized
help clinicians to recognize potential complications, and to provide clear guidance on optimum treatment pathways. treatment plans with multimodal approaches, where cultural and ethnical backgrounds are important. Aesthetic
All aesthetic physicians should be prepared for the eventuality of filler complications, despite their rarity.9 physicians must also understand the person behind the patient so that they can provide the treatment outcome that
they will be most satisfied with. Using technological advancements such as ‘big data’ and artificial intelligence, we
Chapter 9 presents a similar algorithm-based approach to vascular complications after CaHA injection. These may see a shift toward individualized treatment plans that consider much more than the standard consultation of today.
recommendations were developed as an international consensus with 17 experts from various continents. As
intravascular injections can cause the most serious adverse events after filler injections and as CaHA has as yet
no proven reversing agent, the use of hyaluronidase as the standard antidote for HA fillers is not applicable. For Products, instruments and diagnostic tools
prevention of intra-arterial CaHA injection, consensus members outlined the importance of a thorough knowledge
of facial vascular anatomy and patient history, as well as highlighting potential risk zones and optimal injection Technological advancements are developing at a rapid rate and a high percentage of the gross turnover of
techniques. Individual sections document how to recognize the symptoms of vascular occlusion leading to vision loss pharmaceutical companies is invested in research and development for new or improved products and instruments.
and tissue necrosis as well as detailed treatment protocols for the management of these events. For impending tissue The biocompatibility of products is becoming increasingly understood at a molecular and immunological level, novel
necrosis, recommendations are provided for early and delayed presentations with treatment protocols for acute and cross-linking techniques are being developed and product types tested. The new European legislation concerning
follow-up treatment. A separate section details the treatment options for open and closed wounds that may arise after medical devices is increasingly strict, demanding long-term clinical follow-up of patients before providing CE mark
intravascular injection with late presentation.10 Having this protocol in the office helps increasing patient safety as certification.12 This ensures increased patient safety as companies are no longer able to extrapolate CE marks from
immediate action is usually required should a vascular event occur. We hope to have contributed to patient safety by previously CE marked products to those about to be launched.
providing these clear recommendations.
Biostimulatory agents such as CaHA activate the patient’s own fibroblasts to produce new collagen and elastin fibers,
Finally, Chapter 10 presents an expert consensus on the use of the CPM-HA range of products with their varying as well as induce differentiation of fibroblasts into myo-fibroblasts, and stimulate neovascularization for increased
rheological properties. The consensus covers various facial indications including the forehead, temples, superior tissue perfusion. This regenerative effect may well be the new path that aesthetic medicine will follow. Possible
and inferior orbital hollows, pre-auricular hollowing, radial cheek lines, marionette lines and sunken corners of the combination with the patient’s own growth factors may prove to improve the effect of biostimulatory products in
mouth, chin, jawline, lip contouring and perioral lines, and skin boosting/revitalization divided into two publications.11 the future. Aesthetic physicians are increasingly adding energy-based devices to their injectables practice and they
Together, this panel of international experts has decades of combined clinical experience and putting them together to are combined with fillers on a daily basis. These make use of the tissue’s regenerative properties and include lasers,
discuss optimizing patient safety by choosing the right product, the right instrument and the right technique provides a radio frequency devices and focused ultrasound.8 Human-identical hormone replacement therapy is another recent
valuable resource for aesthetic physicians around the world. addition that is increasingly prescribed.13 New insight into autologous cells such as adipose-derived mesenchymal
stem cells is accumulating and in the future the field of regenerative medicine may become as important to aesthetic
Taken together, these chapters represent a comprehensive resource for clinicians wanting to improve their aesthetic medicine as soft tissue fillers currently are.14 There have also been significant diagnostic advances at both the
techniques and improve patient safety during facial filler treatments in aesthetic medicine. cellular and genomic level that may be beneficial to the aesthetic practitioner. Production of immunologically active
substances such as cytokines have been linked to the degree of cross-linking and particle size of HA fillers15 In the
future, we may see commercially available immunological tests targeting markers (such as major histocompatibility
complex) linked to specific product-related complications, for example, late inflammatory reaction syndrome (LIRS,
Chapter 8). In the future it may be possible to perform a DNA test prior to treatment to diagnose the potential risk
of an immunologic reaction to certain filler types and to diagnose a patient’s genetic aesthetic weaknesses. Using
future epigenetic therapeutic options, it may become possible to switch specific genes in specific cell types on or off
without altering the DNA.16 Other treatments may allow specific peptides to be topically introduced to the dermis,
to address problems such as hyperpigmentation, sebum production, moisturization, skin reactivity as well as other
aesthetic problems. The field of topical skin care is therefore likely to become increasingly important in the future,
as prescription topicals will have much more effect than currently available over-the-counter products, which are
limited by permitted levels of penetration, concentration and efficacy.17 Nanotechnology and other new technologies
to deliver active cosmeceutical ingredients and prescription topicals to target sites may prove to play important roles
in the future.18 Recently, pressurized gas injectors have been used by aestheticians to inject HA into the lips and
wrinkles. This attempt at needle-free injecting was initially a big success, emphasizing the potential for treatment
modalities that do not involve needles for introducing fillers. However, the device propels the gel with a speed of
800 km/h through the dermis, and produced some severe vascular problems which led to a silent retreat from the

226 general discussion 227

 impact of this thesis and future developments
aesthetic market. Nonetheless, this example highlights the demand for injection devices without needles and research Treatment techniques
is ongoing to develop new instruments that will address this need.19
Throughout medicine, there is a general shift towards minimally-invasive procedures to reduce downtime and
The blunt cannula is becoming the gold standard for the experienced and well-trained physician, with sharp needle optimize patient safety and comfort. As products, instruments and diagnostic tools evolve, techniques will naturally
use declining. The disadvantage of blunt cannulas is the required learning curve, and for experienced needle-users, evolve with them. At present, we are observing a shift towards the use of non-traumatic cannulas. Furthermore,
the switch to cannulas is not appealing.4 Further improvements in cannulas may include special trocars for easy while sharp needles have become thinner over the years, non-traumatic cannulas are becoming thicker due to safety
entry to deeper tissue layers, or changes in tip shape to address specific needs. We might also see the development considerations and insights into anatomy. Results from cadaver studies show that 22-25G cannulas are much safer
of cannulas that can conduct electrical currents through their tip to create heat in combination with injection of than the smaller gauge 27G as they are significantly less prone to enter blood vessels.26 The 30G cannula is virtually
neocollagenesis-stimulating products. absent in clinics today, and while the 27G cannula still has a place in some indications such as the vermillion border
of the lips, the 22-25G cannulas are now becoming the gold standard in aesthetic practice.
Ultrasound devices are now almost standard equipment for any aesthetic physician and their direct visualization
can be used preventatively to precisely inject a reversing agent for a filler that is located intravascularly or as a As bone resorption plays an important role in the aged appearance of the face, new techniques will undoubtedly be
nodule. The enthusiasm of using these ultrasound devices may sometimes, however, result in unrealistic feelings devised to correct this hard tissue volume loss with the appropriate products to match the technique of subperiosteal
of safety when used to avoid intravascular injection.20 Even Doppler devices have limited precision and may not injection where the osteoblasts reside, with or without direct (endoscopic) visualization.
visualize every small blood vessel. Moreover, even though these devices can visualize arteries, actual injection while
performing visualization is difficult, especially when the goal is to inject extravascularly. Injection of fillers under
ultrasound control restricts the physician’s aesthetic assessment of the amount of product necessary to achieve the Management of complications
aesthetic result and increases treatment time dramatically. While appreciating the potential benefit in the future, I
do not actively promote ultrasound visualization for prevention of complications due to these restrictions. However, Complications are relatively rare, but they do occur. The algorithms presented in this thesis are partly based on hard
the technology will continue to undergo improvements and may become a beneficial part of visual inspection and scientific evidence and partly on consensus, best practice, and expert opinions. As the field of aesthetic medicine
aesthetic assessment of our patients in the future. Advances in ultrasound technologies and other radiological imaging advances, more will be learned about complications and how to manage them, and the suggestions may change over
modalities such as MRI and CT may lead to their greater use in the clinics of aesthetic physicians. When combined time. New insights have led to general recommendations for the prevention of complications such as minimizing
with Augmented Reality devices such as Google Glass or Microsoft HoloLens, stereo ultrasound devices or other bolus volume to 0.1 ml per bolus, or 0.025 ml in the periorbital area close to the supraorbital notch. It is likely that in
radiologic technologies may provide the aesthetic practitioner with real-time visualization of anatomical layers the near future, new anatomical discoveries will be made that will lead to further recommendations for preventative
and anatomical structures while the product is being injected into the tissues. In the future, the treating physician measures to minimize risk of complications and optimize patient safety.
may wear a head-set or pair of ‘smart glasses’ that project images onto the glasses to provide a layer of additional
information, and which may even include alerts when approaching a dangerous structure with the needle positioned One product that has been discussed frequently in this thesis, CaHA, currently has no proven reversing agent. With
in the tissue.21 investigations underway for possible candidates, we may soon find an agent that is capable of fast dissolution of
CaHA 27. When this is found, it may impact the market greatly, as product-related complications such as granuloma
3-D photography is also developing rapidly and can be used as a diagnostic tool to quantify the amount of lift or formation are significantly less common after CaHA than with all other fillers on the market, making CaHA one of the
volume necessary, as well as to assess results after the treatment.22 Real-time 3-D photography or videography may safest soft tissue filler products available.3
even represent the start of long-distance treatments with robotic injection arms where a physician on the other side of
the globe uses virtual reality glasses to treat the real patient from a virtual environment.
Concluding remarks
Advances in synthetic product development are continuing and aesthetic medicine is looking at other specialties
including plastic and orthopedic surgery, where 3-D printed scaffolds are being produced. The technical possibilities Aesthetic medicine is a new medical field that draws a line between science, technical skills and art. As the word
of tweaking material properties are increasing and in the future it may be possible for an injectable, or at least physician in dutch (“arts”) has been etymologically linked to the word “artist”, it seems fitting that aesthetic physicians
minimally-invasive insertable implant that is highly biocompatible to be produced with a specific shape, based on should possess a creative and artistic talent. Physicians often have an artistic side that is typically practice as a hobby,
the patient’s own anatomy and aesthetic wishes. It could be conceived that while the product is liquid or gel-like on whether it be painting, drawing, creating music, sculpting, etc. Many physicians also have a natural affection for the
periosteal injection, it solidifies with a specific signal to become structural support for overlying soft tissues. arts. The field of aesthetic medicine offers physicians with an interest and talent in art and aesthetics to combine this
with their medical and scientific educational background. The way light reflects off the skin, from highlights, through
Anesthetic products and tools are also undergoing advances. The “gate control” theory suggests that pain can transitional shadow to shadow lines; the shape of curves and lines, and the balance of facial elements and proportions
be reduced by simultaneous activation of nerve fibers that conduct non-noxious stimuli. Other medical fields as of facial structures are all extremely important for the aesthetic physician, but relatively non-scientific. There have
obstetrics have advanced in non-pharmacological pain reduction methods and aesthetic medicine may play a role been a few attempts to capture beauty and attractiveness as scientific formulas, and there are publications in medical
in further development of alternative ways of pain reduction.23 Specific brainwaves may be measured to diagnose journals on facial proportions with the most convincing being that of the golden ratio.28 This can be found in nature
pain perception and linked to vibration frequencies that target specific areas on the face or body to reduce pain and is therefore sometimes referred to as the Divine Proportion, and has been used in art for centuries. It is derived
perception. Hypnosis techniques may also be of value in the future as the suggestion of no pain perception under from the Fibonacci sequence and has been used to create beauty and balance in architecture, sculpture, fashion,
hypnosis actually works as does the placebo effect.24 New pain-reducing devices have also been reduced such as painting, drawing as well as other forms of art. In aesthetic medicine, treatment approaches using this proportion have
the CoolSense cooling device.25 Innovations include the integration of this cooling method into injection systems been developed. Golden ratio calipers are available and there is even is a golden ratio mask, designed to objectify
for mesotherapy and shape improvements for specific areas such as the lips. Further developments can also be facial beauty and suggest treatment strategies.29 Future research may bring the subjective world of art, where beauty is
imagined, for example special facial shape masks with specific dermal connection points where the application in the eyes of the beholder, closer to the objective world of science, where there is only one truth.
of low temperature and vibration anesthetize the skin.

228 general discussion 229

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areas of the body. Dermatol Surg. 2016;42(10):1199– apparatuur-o-a-hyaluronpen-en-plexr-door-niet-artsen/ 27. Robinson DM. Dissolving calcium hydroxylapatite filler
1208. (consulted June 7th, 2019) using sodium thiosulfate: preliminary observations.
9. Snozzi P, Van Loghem JAJ. Complication Management 20. Schelke LW, Decates TS, Velthuis PJ. Ultrasound to Dermatol Surg; in press.
following Rejuvenation Procedures with Hyaluronic Acid improve the safety of hyaluronic acid filler treatments. 28. Prokopakis EP, Vlastos IM, Picavet VA, Nolst Trenite G,
Fillers—an Algorithm-based Approach. Plast Reconstr Surg J Cosmet Dermatol. 2018 Dec;17(6):1019-1024. doi: Thomas R, Cingi C, Hellings PW. The golden ratio in facial
Glob Open 2018;6:e2061. 10.1111/jocd.12726. Epub 2018 Aug 6. symmetry. Rhinology. 2013 Mar;51(1):18-21. doi: 10.4193/
10. Van Loghem JAJ et al. Consensus on the use of fillers from 21. Marker DR, U Thainual P, Ungi T, Flammang AJ, Fichtinger Rhino12.111.
the Belotero CPM range: best practice in specific facial G, Iordachita II, Carrino JA, Fritz J. 1.5 T augmented 29. Dayan SH. What is beauty, and why do we care so much
indications. 2 manuscripts under review reality navigated interventional MRI: paravertebral about it? Arch Facial Plast Surg. 2011 Jan-Feb;13(1):66-7.
11. Van Loghem JAJ et al. Managing Intravascular sympathetic plexus injections. Diagn Interv Radiol. 2017 doi: 10.1001/archfacial.2010.65.
Complications Following Treatment with Calcium May-Jun;23(3):227-232. doi: 10.5152/dir.2017.16323.

230 general discussion 231

 Appendices
• Nederlandse Samenvatting
• English Summary
• Protocol for a Global Facial Approach
• The Crash Kit for Filler Complications
• List of Publications, Co-authors and Their Contributions
• Curriculum Vitae
• Portfolio
• Acknowledgements

232 appendices 233

 nederlandse samenvatting
Dit proefschrift beschrijft een onderzoek naar het veiliger maken van behandelingen met afbreekbare vulmiddelen In Hoofdstuk 8 worden diverse complicaties besproken die na HA-filler-injecties kunnen optreden. Het is lastig om
(fillers) voor cosmetisch geneeskundige indicaties in het gelaat. behandeling van complicaties te starten als er nog geen diagnose is gesteld. Met de algoritmes die in dit hoofdstuk
In Hoofdstuk 1 introduceren we het nieuwe profielspecialisme Cosmetische Geneeskunde en de verschillende worden beschreven, worden op basis van klinische presentatie en diverse flow diagrammen, duidelijke adviezen
deelgebieden die dit vak beslaat. Vervolgens zoomen we in op door het lichaam afbreekbare fillers die worden gegeven om HA complicaties te diagnosticeren en te behandelen.
gebruikt voor cosmetische toepassing in het gezicht. Ook bespreken we wat er bekend is over verschillende
fillerproducten en veiligheidsaspecten hiervan. Daarnaast is er aandacht voor de anatomie gerelateerd aan fillers en Hoofdstuk 9 beschrijft de consensus die 18 internationale experts bereikt hebben op het gebied van injectables. Deze
mogelijke complicaties van fillerbehandelingen. consensus is zowel evidence based als expert based en bevat aanbevelingen voor het behandelen van intravasculaire
embolisatie met CaHA. Aangezien er geen antistof bekend is die dit middel direct kan oplossen zoals bij HA fillers,
In Hoofdstuk 2 gaan we in op een veelgebruikte filler, calciumhydroxylapatiet (CaHA, Radiesse®). Hiervan bespreken ligt veel nadruk op preventie en behandeling van embolisatie. De behandelaar moet hiervoor beschikken over goede
we de geschiedenis, de toepassingen en de ervaring die we hiermee hebben opgedaan in onze kliniek gedurende kennis van de anatomie en injectietechnieken. Er worden drie categorieën embolisatie beschreven: vroeg herkende
tien jaar. Verder geven we een standaard behandelprotocol voor reconstructie van de jeugdige gezichtsanatomie. perifere embolisatie, laat herkende perifere embolisatie (met necrose en wonden tot gevolg) en retinale embolisatie.
Doel hiervan is het bereiken van een zo natuurlijk mogelijk behandelresultaat. Hierbij wordt CaHA in verschillende
verdunningen gebruikt om de diverse verouderingskenmerken te behandelen. Dit gebeurt in diverse anatomische Hoofdstuk 10 beschrijft een expertconsensus voor de behandeling van diverse gezichtsindicaties met de HA-
lagen, van oppervlakkig (dermaal) tot dieper (periostaal). Het protocol richt zich op correctie van diverse producten van de cohesive polydensified matrix (CPM) serie, bekend onder de merknaam Belotero. De producten
verouderingskenmerken in het gelaat. worden beschreven naar hun rheologische eigenschappen. Per indicatie worden op basis van het gewenste effect,
rheologische producteigenschappen, anatomie en anatomische gevarenzones, aanbevelingen gedaan voor de keuze
In Hoofdstuk 3 worden instrumenten vergeleken die veel worden gebruikt voor periostale injectie van fillers: scherpe van het product en de behandeltechniek.
naalden versus stompe canules. Deze vergelijking maakten we door bij vier kadavers vijf anatomische gebieden
te injecteren met gekleurde gels: de frontale regio, de temporale regio, de infra-orbitale regio, de mandibula en Tezamen geven deze 10 hoofdstukken een verdieping van de kennis over de optimalisatie van patiëntveiligheid tijdens
het mentum. Vervolgens vond dissectie van deze regio’s plaats. Belangrijke conclusies van dit onderzoek waren fillerbehandelingen voor cosmetische toepassingen in het gelaat.
dat stompe canules veiliger leken dan scherpe naalden en dat canules preciezer waren in het voorspellen van het
anatomische niveau waar de filler uiteindelijk terecht komt.

In Hoofdstuk 4 nemen we een standaard veiligheidstest onder de loep. Aspiratie voorafgaand aan injectie lijkt op het
eerste gezicht een effectieve manier om uit te sluiten dat een naald niet in een bloedvat gepositioneerd is. Echter, dit
geldt voor injectievloeistoffen die een lage visco-elasticiteit hebben. In dit in vitro-onderzoek testten wij veelgebruikte
injecteerbare fillers – bestaande uit gels met een bepaalde stroperigheid – en diverse naalden met verschillende diktes
en lengtes. Uit het onderzoek bleek dat bij aspiratie van 1 seconde, 67% van de geteste producten met verschillende
naalden, vals-negatieve resultaten bleek te geven. Hierdoor konden we concluderen dat de sensitiviteit van de
aspiratie test afhankelijk was van het fillerproduct en de gebruikte naald en dat een negatieve aspiratie test over het
niet garandeert dat een naald niet in het bloedvat zit.

In Hoofdstuk 5 wordt een retrospectieve analyse besproken over 1 jaar van 70 patiënten die gedurende dat
jaar werden behandeld met CaHA in het bovenste derde deel van het gezicht: voorhoofd, slapen en/of laterale
wenkbrauwen. Dit is geen standaard indicatiegebied voor CaHA en hier is niet veel over gepubliceerd. Daarom
zijn de resultaten uit deze analyse een waardevolle toevoeging aan de schaarse kennis die er is: de besproken
verdunningen en canuletechnieken leverden goede resultaten op en ernstige complicaties traden niet op.

In Hoofdstuk 6 werd de pijnbeleving tijdens behandelingen per injectie gemeten met een visuele analoge score. Er
werd gekeken naar verschil in pijnbeleving tussen de linker- en rechterzijde. Met 302 patiënten was de groep groot
genoeg om statistisch aan te kunnen tonen dat de linkerzijde gemiddeld gevoeliger is voor pijn dan de rechterzijde.
Verder bleek dat beginnen met de behandeling aan de linkerzijde een significant lagere totale pijnbeleving geeft dan
beginnen aan de rechterzijde.

Hoofdstuk 7 beschrijft een bijeenkomst van een adviesraad waarbij meer dan 400 experts uit meer dan 60 landen
samenkwamen. Doel van deze bijeenkomst was consensus te bereiken over het combineren van de volgende
behandelmethoden in de cosmetische geneeskunde: botulinetoxine, hyaluronzuur (HA), CaHA, gefocust ultrageluid
met echovisualisatie en andere toepassingen. Ook werd deze bijeenkomst benut om best practices te omschrijven
waarbij combinatie van deze behandelmethoden werd toegepast. Verder worden diverse presentaties beschreven
over behandelingen van uiteenlopende gezichts- en lichaamsindicaties. Doel van deze behandelingen was om de
meest harmonieuze en natuurlijke resultaten te bereiken.

234 appendices 235

 english summary
The popularity of injectable treatments as a minimally-invasive method of aesthetic rejuvenation and enhancement Chapter 8 describes the potential complications that can occur after HA filler injections and the importance of an
continues to grow in concert with the number of treatment indications. With greater numbers of physicians practicing accurate diagnosis. The chapter’s algorithms provide clear guidance on how to diagnose and treat complications that
aesthetic medicine and increased numbers of treatments performed there will inevitably be a rise in the number and may arise after HA filler injection based on their clinical presentation.
spectrum of adverse events. While most are mild and transient, more serious complications can occur that leave the
patient with long-lasting or permanent injuries. This thesis has been developed as a resource to improve the safety of Chapter 9 focuses on vascular complications and in particular those arising after inadvertent intra-arterial injection
degradable filler injections for facial indications. of CaHA, which unlike HA does not currently have a reversing agent. For this reason, much emphasis is placed on
prevention of vascular compromise, and on treatment of an embolization should it occur. A consensus document
Chapter 1 provides an introduction to the new profile specialty of Aesthetic Medicine and an overview of the efficacy produced by 18 international experts in the field of injectables is described which provides both evidence-based
and safety of biodegradable fillers for facial aesthetic indications. The potential complications of filler injections are and expert-based recommendations for the treatment of intravascular embolization with CaHA: early recognized
described in relation to facial anatomy. peripheral embolization, late recognized peripheral embolization (resulting in necrosis and wounds), and retinal
embolization. Embolization is solely due to injector technique and the chapter highlights the need for all practitioners
Chapter 2 focuses on calcium hydroxylapatite (CaHA, Radiesse®), one of the most widely used dermal fillers with an to have a good knowledge of facial anatomy and appropriate injection techniques.
established history of clinical use. We discuss the applications of this filler and provide advice based on experience
gained in our clinic over the past 10 years. A standard treatment protocol for the reconstruction of a youthful Chapters 10 concludes the thesis with a description of an expert consensus on the use of HA products from the
facial anatomy is provided with the aim of achieving as natural a result as possible. CaHA can be used at various cohesive polydensified matrix (CPM) Belotero range. The products in this range have been designed with specific
dilutions to treat a range of facial indications with injections performed at superficial (dermal) to deep (periosteal) rheological properties. The consensus provides recommendations on the optimal product and treatment technique for
anatomical levels. a range of facial indications based on underlying anatomy and anatomical risks.

Chapter 3 compares the instruments widely used for periosteal filler injection: sharp needles versus blunt cannulas. Together these 10 chapters in this thesis should provide practitioners with a deeper understanding about how to
This was undertaken by injecting four cadavers with colored gels in five anatomical areas: the frontal region, the optimize patient safety during filler treatments for facial aesthetic applications.
temporal region, the infra-orbital region, the mandibula and the mentum. The results of subsequent dissections of
these regions revealed that blunt cannulas appeared safer than sharp needles and were more precise in predicting the
anatomical level (periosteal) of final filler placement.

Chapter 4 examines the value of aspiration prior to injection as a standard safety test. While at first this might seem
an effective method of determining whether the tip of a needle is positioned in a blood vessel, it is only applicable
to fillers with low viscoelasticity. In an in vitro study we performed aspiration with a range of commonly used
injectable fillers of varying viscoelasticity, injected with a range of needle lengths and gauges. The research showed
that with a 1 second aspiration, 67% of the tested products injected with various needles showed false negative
results. The sensitivity of aspiration as a safety test was dependent on both the filler product and the needle, and was
generally low.

Chapter 5 describes the results of a retrospective 1-year analysis of 70 patients treated with CaHA in the upper third
of the face: frontal region, temporal hollows and eyebrows. This is not a standard indication for CaHA and little
has been published about injections in this area. The CaHA dilutions and cannula techniques used provided good
aesthetic results with no serious complications. The results from this analysis are therefore a valuable addition to
the literature.

Chapter 6 focuses on the perception of pain during injection treatments and describes the results of a study that
compared pain perception measured with a visual analogue score on the left and right sides of the face in over
300 patients. The results showed that the left side of the face was statistically more sensitive to pain than the right.
Furthermore, starting treatment on the left side of the face appeared to provide a significantly lower total pain
experience than starting treatment on the right.

Chapter 7 describes the outcomes of an advisory board meeting attended by more than 400 experts from more than
60 countries. Participants discussed best practice for combining treatments including botulinum toxin, hyaluronic acid
(HA), CaHA, microfocused ultrasound with visualization as well as other applications. The meeting also featured a
number of presentations on best practice for treating a variety of facial and body indications with the aim of achieving
harmonious and natural results.

236 appendices 237

 protocol for a global facial approach
Patient safety during facial filler treatments in aesthetic medicine can be improved with the following general injection The main concern are the relevant arteries: the external carotid artery and its branches (superficial temporal artery,
protocol for various facial indications, using non-traumatic cannulas, based on current knowledge of facial anatomy maxillary artery and the facial artery) as well as the ophthalmic artery and its branches (including the supratrochlear
(Figure 1). and supraorbital arteries). The branches of the facial artery (submental, inferior labial, superior labial, lateral nasal
and angular arteries) and the branches of the maxillary artery zygomaticofacial, infraorbital, deep temporal, mental
arteries) have various connections, making it possible to embolism an external carotid branch with displacement into
an internal carotid artery branch; this makes blindness and strokes possible with soft tissue fillers injected in the face.
In the area close to the supraorbital and supratrochlear arteries and their connections to the dorsal nasal and angular
CF: Central forehead entry point. Frontal arteries, extra care should be taken (see Table 1).
concavity (periosteal)
TC: Temporal Crest Entry point. Frontal concavity
(periosteal), temporal hollows (interfascial).
SO: Supraorbital entry point. A-Frame deformity Table 1
and Superior orbital sulcus (submuscular)
LB: Lateral Brow entry point. Lateral Brow lift 1 Use blunt cannulas with 25G thickness or thicker
(periosteal, subcutaneous)
LO: Lateral Orbit entry point. Palpebromalar
Groove (periosteal), Cheek apex (periosteal) 2 Choose the anatomical level where the lowest risk of arterial presence is
TT: Tear Trough entry point. Tear troughs
(periosteal)
NT: Nasal Tip entry point. Nose augmentation 3 Choose a direction of the cannula as perpendicular to the artery as possible
(periosteal)
ZA: Zygomatic Arch entry point. Lateral cheek
(periosteal), zygomatic retaining ligament lift 4 To pass a fascia, some force is allowed
(periosteal)
MZ: Medial Zygoma entry point. Medial cheek
(periosteal, in the deep medial cheek fat 5 After reaching the desired anatomical level, no force should be used (“tea-time technique”)
compartment)
MA: Mandibular Angle entry point. Mandibular
contouring (subcutaneous), masseter 6 When the cannula tip reaches a resistance, a gentle, back and forth motion, combined with a rolling
augmentation (periosteal) technique (the “pencil-rolling technique”) should be used to pass resistances without using force
NL: Nasolabial entry point. Nasolabial fold
(periosteal, subcutaneous) 7 Take extra care near neuromuscular bundles, scars and other reasons for having tight tissue
OC: Oral Commissure entry point. Lips around the artery that may prevent pushing the artery aside
(subcutaneous), lip lift (periosteal), oral
commissures (subcutaneous) 8 Around the supratrochlear arteries, use the non-dominant thumb and index finger to press on the
PS: Prejowl Sulcus entry point. Prejowl supratrochlear arteries to temporarily block blood flow (and prevent embolus displacement)
sulcus (subcutaneous), marionette lines
(subcutaneous), mental crease (subcutaneous) 9 Inject low volumes (0.025 ml or less per retrograde linear thread) to reduce chance of reaching
MM: Midline Mentum entry point: Pogonium the central retinal artery
projection (periosteal), mentum (subcutaneous,
periosteal) 10 Inject slowly to reduce chances of retrograde displacement of the embolus against the blood
stream of the ophthalmic artery branches.
Figure 1
Injection schematics for a global facial approach. Pink: deep, purple: superficial placement of soft tissue The ten commandments of soft tissue filler injections
fillers.
Abbreviations are shown on the right along with the facial indications from that entry point as well as the
desired depth of placement. SO: Supraorbital foramen, ST: Supratrochlear foramen, ZF: Zygomaticofacial
foramen, ZT: Zygomaticotemporal foramen (behind lateral orbit), IO: Infraorbital foramen, M:
Mental foramen.

238 appendices 239

 the crash kit for filler complications
In order to optimize safety for soft tissue filler injections, firstly, the facility must meet the minimum requirements as
stated by the Dutch Society of Aesthetic Medicine (https://nvcg.nl/download/nvcg-veldnorm-minimalen-vereisten-
voor-de-faciliteit-en-omstandigheden-voor-cosmetische-artsen-versie-3-sept-2017/).

The treating physician should be trained annually in Basic Life Support and preferably have annual practice of
management of acute filler complications. Protocols for management of acute situations in the aesthetic practice
should be available and basic medical equipment should be readily available like an AED, blood pressure
meter, stethoscope, tourniquet, infusion needle, syringes, needles, saline and medications for shock (adrenalin,
corticosteroids, antihistamines) and epileptic seizures (diazepam rectiole) should be available in the facility. An
ultrasound device with Doppler is recommended for treatment of intra-arterial embolizations.

Table 1

Filler-related acute Treatment Medication (in Netherlands)

medical condition

Hematoma / bleeding Apply direct pressure -

for several minutes

Syncope Stop treatment, position patient -

in Trendelenburg and observe
until recovery

Retinal ischemia Follow protocols as described Hyaluronidase 1500U, 4 vials

in Chapters 8 and 9 Aspirin 500 mg
Timolol 0.5% with brinzolamide
1% eyedrops.

Peripheral ischemia Follow protocols as described Hyaluronidase 1500U, 10 vials

in Chapters 8 and 9 Aspirin 500 mg tablets.

Anaphylactic reaction Follow protocol as described Epipen (0.3 mg adrenalin i.m.)

in Chapter 8 Clemastin 2 mg i.v.
Prednisolone 50 mg i.v.

Hypersensitivity (allergic) reaction Follow protocol as described Prednisolone 50 mg tablets

in Chapter 8

Acute medical conditions that are directly related to soft-tissue filler treatments

240 appendices
 list of publications, co-authors
and their contributions curriculum vitae
Calcium hydroxylapatite: over a decade of clinical experience. Jani van Loghem, former vice-chairman of the Dutch Society of Aesthetic Medicine (NVCG) up to January 2020, Head
Van Loghem JAJ, Yutskovskaya YA, Philip Werschler W. J Clin Aesthet Dermatol. 2015 Jan;8(1):38-49. of the Department of Aesthetic Medicine of the European College of Aesthetic Medicine and Surgery (ECAMS), and
JVL contributed to the text, provided the clinical pictures, the injection schematics and wrote the manuscript. YAY member of the esteemed Expert2expert group, specializes minimally invasive aesthetic treatments such as injectables,
contributed to the text, PWW contributed to the text. liposuction, lasers and chemical peels. Jani has been actively involved in creation of the content and execution of
a 2-year curriculum of the new official medical profile specialty Aesthetic Medicine, which is held at the Academic
Cannula Versus Sharp Needle for Placement of Soft Tissue Fillers: An Observational Cadaver Study. Medical Center in Amsterdam and recognized by the Dutch government.
Van Loghem JAJ, Humzah D, Kerscher M. Aesthet Surg J. 2016 Dec 16. pii: sjw220.
JVL contributed to the text, provided the clinical pictures, the injection schematics images and wrote the manuscript. Jani: "I see the field of Aesthetic Medicine as a new medical specialty. I take my patients just as seriously as any other
DH contributed to the text, MK contributed to the text. specialist does. Aesthetic Medicine is a fast growing and exciting field and I want to be part of its development."

Sensitivity of aspiration as a safety test before injection of soft tissue fillers.

Van Loghem JAJ, Fouché JJ, Thuis J. J Cosmet Dermatol. 2018 Feb;17(1):39-46. Experience
JVL contributed to the text and wrote the manuscript. JJF contributed to the text, JT contributed to the text.
Even before Jani graduated from medical university, he was already trained in injectable treatments in early 2004.
Use of calcium hydroxylapatite in the upper third of the face: Retrospective analysis of techniques, dilutions and After his medical studies, Jani worked as a junior doctor in general surgery and aesthetic plastic surgery. He learned
adverse events. working with aesthetics in different private clinics and through many congresses, conferences, training courses
Van Loghem JAJ. J Cosmet Dermatol. 2018 Oct 25. doi: 10.1111/jocd.12733. and workshops. From his background as a medical biologist and his interest to dive deeply into the literature, he
JVL contributed to the text, provided the clinical pictures, the injection schematics images and wrote the manuscript. developed a thorough understanding of the science behind aesthetic medicine, which he applies in daily practice
from his own clinic UMA Institute in Amsterdam, Netherlands. His clinic offers patients a wide variety of procedures;
Left/Right Pain Asymmetry With Injectable Cosmetic Treatments for the Face. from plastic surgery and aesthetic medicine to skin therapy and beautician treatments and is an established
Fouché JJ, Van Loghem JAJ, Thuis J, De Heer LM, van Oijen MGH. Aesthet Surg J. 2017 Jun 1;37(6):708-714. doi: destination for patients seeking quality in the Netherlands and beyond.
10.1093/asj/sjw214
JFF contributed to the text, treated patients included in the study and wrote the manuscript. JVL contributed to the text
and treated patients included in the study. JT contributed to the text and treated patients included in the study. LDH International Key Opinion Leader
contributed to the text, MVO contributed to the text.
At UMA Academy in Amsterdam, Jani receives many dozens of doctors a year from around the world for specialized
Combined aesthetic interventions for prevention of facial ageing, and restoration and beautification of face and body. advanced training programs in injectables. As Head of the Department of Aesthetic Medicine of ECAMS, he is
Fabi S, Pavicic T, Braz A, Green JB, Seo K, van Loghem JAJ. Clin Cosmet Investig Dermatol. 2017 Oct 30;10:423-429. responsible for its cadaver-based injectable courses with the most successful course being the Master Course in
doi: 10.2147/CCID.S144282. Nonsurgical Facial Transformation which is held worldwide. He is a well-known speaker at many international
SF contributed to the text on combination therapy, TP contributed to the text, AB contributed to the text, JBG congresses like AMWC, ISDS, NS-ASAPS, ASAPS, IMCAS, Face2face, WCAD, AMEC, and many more. Jani has been
contributed to the text, KS contributed to the text JVL contributed to the text. traveling the world to visit colleagues to exchange knowledge, tips and tricks with especially the Merz portfolio as a
Global Key Opinion Leader. As a founding Global Faculty Member, Jani has laid the foundations of the international
Complication Management following Rejuvenation Procedures with Hyaluronic Acid Fillers—an Algorithm-based training program of the Merz Institute of Advanced Aesthetics and is actively involved in the development of many
Approach. training programs offered by Merz. At UMA Institute, Jani is conducting clinical research for his PhD thesis at the
Snozzi Ph, Van Loghem, JAJ. Plast. Reconstr. Surg. GO. 2018;6:e2061 department of Ophthalmology of Amsterdam University Medical Center focusing on optimizing safety during facial
PS contributed to the text and wrote the manuscript. JVL contributed to the text. filler treatments.

Managing Intravascular Complications Following Treatment with Calcium Hydroxylapatite: An Expert Consensus.
Van Loghem JAJ, David Funt, Tatjana Pavicic, Kate Goldie, Yana Yutskovskaya, Sabrina Fabi, Pieter Siebenga, Job
Thuis, Peerooz Saeed, Joseph Hkeik, Jonathan Kadouch, Welf Prager, Nabila Azib, Gabriela Casabona, Steve Dayan,
Shino Bay Aguilera, Philippe Snozzi. J Cosmet Dermatol. 2020 Mar 17. doi: 10.1111/jocd.13353.
JVL contributed to the text and wrote the manuscript. All other authors contributed to the text.

Consensus on the use of hyaluronic acid fillers from the cohesive polydensified matrix range: best practice in specific
facial indications
Van Loghem JAJ, Casabona G, Cotofana S, Fabi SG, Goldie K, Gout U, Kerscher M, Lim TS, Pavicic C, Pecora C,
Sattler G, Sattler S, Trindade de Almeida A, Wanithhakdeedecha R, Werschler P, Pavicic T.
(Final draft)
JVL contributed to the text and wrote the manuscript. All other authors contributed to the text.

242 appendices 243

 curriculum vitae
Curriculum Vitae • Sensitivity of aspiration as a safety test before injection of soft tissue fillers. Van Loghem JAJ, Fouché JJ, Thuis J. J
Cosmet Dermatol. 2018 Feb;17(1):39-46. [First author]
Name: Jani Adriaan Joghem van Loghem, MD • Use of calcium hydroxylapatite in the upper third of the face: Retrospective analysis of techniques, dilutions and
Date of birth: March 14, 1972 adverse events. Van Loghem JAJ. J Cosmet Dermatol. 2018 Oct 25. doi: 10.1111/jocd.12733. [First author]
Residence: Amsterdam, Netherlands • Combined aesthetic interventions for prevention of facial ageing, and restoration and beautification of face and
Nationality: Netherlands body. Fabi S, Pavicic T, Braz A, Green JB, Seo K, van Loghem JA. Clin Cosmet Investig Dermatol. 2017 Oct
Business address: Falckstraat 51, 1017VV Amsterdam 30;10:423-429. doi: 10.2147/CCID.S144282.
E: [email protected] T: +31208454525 Cell: +31624687322 • Complication Management following Rejuvenation Procedures with Hyaluronic Acid Fillers—an Algorithm-based
Approach. Snozzi Ph, Van Loghem, JAJ. Plast Reconstr Surg Glob Open. 2018 Dec 17;6(12):e2061.
[Second author]
Education, memberships and medical experience • Managing Intravascular Complications Following Treatment with Calcium Hydroxylapatite: An Expert Consensus.
Van Loghem JAJ et al. J Cosmet Dermatol. 2020;00:1–14.. [First author]
• PhD candidate Opthalmology (University of Amsterdam, 2017-present) • Consensus on the use of hyaluronic acid fillers from the cohesive polydensified matrix range: best practice in
• Medical Biologist (Master of Science degree – University of Amsterdam, 1999) specific facial indications . Van Loghem JAJ, et al. (Final draft) [First author]
• Medicine (Master of Science degree – University of Utrecht)
• Medical Doctor (University of Utrecht, 2005)
• Training General Surgery (2006) Published national guide lines
• Training Aesthetic Plastic Surgery (2007 – 2008)
• Member of the Dutch Society of Cosmetic Surgery NVVCC (www.nvvcc.nl) • NVCG Standaard voor Botuline toxine type A injectietherapie in de Esthetische Geneeskunde: een
• Member (2008-present) and W (2015-january 2020) of the Dutch Society of Cosmetic Medicine NVCG Multidisciplinaire Consensus (first author and chairman of the consensus group)
(www.nvcg.nl) • Veldnorm Autologe PRP (member of the consensus group)
• Founding member of the Netherlands Foundation of Esthetic Medicine (www.nseg.nl) • NVCG VELDNORM MINIMUM VEREISTEN VOOR DE FACILITEIT EN OMSTANDIGHEDEN VOOR
• Vice president of the Foundation of Cosmetic Medical Training (SOCG; 2017-2020) COSMETISCH ARTSEN (first author and chairman of the consensus group)
• Coordinator of the Module Injectables for the 2-year NVCG curriculum • NVCG Veldnorm voor Cosmetisch gebruik van niet-lichaamseigen, afbreekbare fillers (first author and chairman
• Chairman: Product and Complication Registration Committee NVCG (2011-2016) of the consensus group)
• Chairman: Educational Committee NVCG (2013-2016)
• Basic trainer (Allergan, 2010)
• Key Opinion Leader and international trainer (Merz Aesthetics 2009 - present) Other interests
• Member: Expert2expert Group (www.expert2expert.co.uk; 2014-present)
• Head of the department of Aesthetic Medicine: European College of Aesthetic Medicine and Surgery (ECAMS, • Health and nutrition
www.ecamedicine.com 2017-peresent) • Diving (Padi open water scuba instructor and BLS instructor)
• Lead trainer at UMA Academy, also known as Falck Academy, previously Doctors Inc Academy (2009-present) • Electronic music (producer and DJ)
• Medical Education Faculty member / Merz Aesthetics Medical Advisory Board • Yoga and high-intensity interval training
• One of 4 founding members of the Global Faculty members of the Merz Institute of Advanced Aesthetics

Publications

• Causes and distribution of facial fractures in a group of South African children and the value of computed
tomography in their assessment. van As AB, van Loghem AJ, Biermans BF, Douglas TS, Wieselthaler N, Naidoo S.
Int J Oral Maxillofac Surg. 2006 Oct;35(10):903-6. [Second author]
• Calcium hydroxylapatite: over a decade of clinical experience. Van Loghem J, Yutskovskaya YA, Philip Werschler
W. J Clin Aesthet Dermatol. 2015 Jan;8(1):38-49. [First author]
• Minimally invasive combination treatment with toxin and filler and its impact on perceived attractiveness and
age. Kerscher, M. Van Loghem J. et al. EADV 2016. ePoster. [Second author]
• Cannula Versus Sharp Needle for Placement of Soft Tissue Fillers: An Observational Cadaver Study. van Loghem
JA, Humzah D, Kerscher M. Aesthet Surg J. 2016 Dec 16. pii: sjw220. [First author]
• Left/Right Pain Asymmetry With Injectable Cosmetic Treatments for the Face. Fouché JJ, Van Loghem JAJ, Thuis J,
De Heer LM, van Oijen MGH. Aesthet Surg J. 2017 Jun 1;37(6):708-714. doi: 10.1093/asj/sjw214. [Second author]
• Use of Calcium Hydroxylapatite for Augmentation of the Labia Majora and Mons Pubis. Jani AJ. van Loghem. SRL
Dermatol Clin Res. 2017;2(1): 010-013. [First author]

244 appendices 245

 portfolio
Name PhD student: Jani van Loghem 3. Parameters of Esteem
PhD period: April 2018-October 2020
Name PhD supervisor: Prof. dr. R.O. Schlingeman, Peerooz Saeed Year

Grant
1. PhD training -

Year Workload Awards and Prizes

(Hours/ECTS) • Best Paper Award Journal of Plastic and Reconstructive Surgery Global Open 2018
General courses

4. Publications
Specific courses
• Course days of the Dutch Society of Aesthetic Medicine (injectables, cosmetic 2018 - 2019 12 Year
dermatology, laser light and energy-based devices, cosmetic surgery)
• 2-day course for the Dutch Society Profile Specialty transitional arrangement 2018 12 Peer reviewed
• Delayed Inflammatory Reactions to Hyaluronic Acid Fillers: A Literature Review and Proposed Treatment 2020
Seminars, workshops and master classes Algorithm. Clinical, Cosmetic and Investigational Dermatology 2020:13
• ECAMS facial transformation course M21 2018 - 2019 • Managing intravascular complications following treatment with calcium hydroxylapatite: An expert consen- 2020
• Merz Aesthetic seminars, workshops and webinars 2018 - 2020 36 sus. J Cosmet Dermatol. 2020;00:1–14.
90 • Complication Management following Rejuvenation Procedures with Hyaluronic Acid Fillers—an Algo- 2018
Presentations rithm-based Approach. Plast Reconstr Surg Glob Open 2018;6:e2061
• Use of calcium hydroxylapatite in the upper third of the face: retrospective analysis of techniques, dilutions and 2018
(Inter)national conferences adverse events. J Cosmet Dermatol. 2018;1–6.
• AMWC 2028 18 • Sensitivity of aspiration as a safety test before injection of soft tissue fillers. J Cosmet Dermatol. 2017;1–8. 2017
• IMCAS 2018-2020 54 • Use of calcium hydroxylapatite for augmentation of the labia majora and mons pubis. Sci J Clin Res Dermatol. 2017
• NVCG congress 2018-2019 12 2017;2(1): 010-013.
• NVCG Seminar 2018-2019 12 • Left/right pain asymmetry with injectable cosmetic treatments for the face. Aesthet Surg J. 2017 Jun 2017
• ADAC Kuala Lumpur 2018-2019 24 1;37(6):708-714.
• GALAA Asia 2018-2019 24 • Combined aesthetic interventions for prevention of facial ageing and restoration and beautification of face and 2017
• MEXS 2018-2019 12 body. Clin Cosmet Investig Dermatol. 2017;10:423-429.
• Cannula versus sharp needle for placement of soft tissue fillers: an observational cadaver study. esthet Surg J. 2017
Other 2017 Dec 13;38(1):73-88
- • Calcium hydroxylapatite: over a decade of clinical experience. J Clin Aesthet Dermatol. 2015 Jan;8(1):38-49. 2015
• Causes and distribution of facial fractures in a group of South African children and the value of computed 2015
2. Teaching
tomography in their assessment. Int J Oral Maxillofac Surg. 2006 Oct;35(10):903-6.
Year Workload Other
(Hours/ECTS) • Minimally invasive combination treatment with toxin and filler and its impact on perceived attractiveness and 2016
Lecturing age. Poster at EADV Vancouver, October, 2016
• UMA Academy 2018-2019 30 • Calcium Hydroxylapatite Soft Tissue Fillers Expert Treatment Techniques. Hardcover textbook and ebook. 2020
• ECAMS 2018-2019 30 Book will ship after November, 2020
• NVCG Seminar 2018-2019 4
• NVCG Congress 2018-2019 4
• MEXS 2018-2019 4
• ADAC Kuala Lumpur 2018-2019 4
• GALAA Asia 2018-2019 12

Tutoring, Mentoring
• ANIOS and AIOS training for NVCG Courses 2018-2019 30

Supervising
• In clinic staff 2018-2019 80

Other

246 appendices 247

 acknowledgements
Even though I didn’t think I would ever embark on a PhD project, I was actively reading the medical literature that The Dutch doctors who are pushing the boundaries of aesthetic medicine and keep The Netherlands ahead of the
was available on aesthetic medicine. When I asked Peerooz Saeed a few years ago for a login to the University game: Tom Decates, Peter Velthuis, Leonie Schelke, Jonathan Kadouch, Tom van Eijk, Frodo Gaymans, Talat Kara, Bart
Library, he gave me one of his wise, professor-like smiles and told me “Yes, that is possible”. The only thing I had to Biermans, Maartje de Bie, Marguerite van Randwijck, Robert Boonen, Annemarie van Rosmalen, Christopher Brandt,
do was to enroll as a PhD candidate. “You’re already doing so much research, it will be easy for you” is what he said. Hayri Hortoglu, Leo van Rozelaar, Peter Termohlen, Don Smeets, Thanya Tha-In, Fred Tjan, Paul Wijffels and Gabriel
I love the fact that you made it seem so simple and doable, conveniently leaving out the reality of sleepless nights Siquier Dameto.
working on the projects, otherwise I might have decided not to pursue this adventure. Peerooz, I especially liked the
dinners we had during our PhD progress meetings and the special wines we drank while talking about life and the The new pioneering Dutch doctors who have and successfully finalized the 2-year training program organized by
research projects. Let’s keep on doing that for years to come. Thank you Peerooz, not only for being my co-promotor the Dutch Society of Aesthetic Medicine: Job Thuis, James Fouché, Maarten Façee Schaeffer, Shailindra Rambaran,
alongside my promotor Reinier Schlingemann at the Amsterdam University Medical Center but also for being the Leanne Wong, Camiel Zeijen and Margaritha Adams.
best oculoplastic surgeon in the world and for having chosen UMA Institute as your private clinic of choice.
The invaluable team at the clinic Sietske Atsma, Samantha van Schaaik, Gijs Naardin, Romain Bilde, Noa Muijsers,
I want to thank my family; my grandparents for inspiring me to dive into science, my parents for who I have become, Adelien Hiensch, Casper van der Linden and Ela Opoka.
my sisters for their challenges, my wife for loving me with all my flaws and my son for making me see the world in a
completely new way. My friends at Merz: Philip Burchard, Kristel Hectors, Josine Bolenius, Andreas Meyer, Yannick Grosskreutz, Tim
Schmidt-Lange, Olga Avdoshina, Simone Arnold, Christian Lauer, Daniel Zeisberger, Owen Sunga, Clifton Tay,
I want to thank the board of the Dutch Society of Aesthetic Medicine: Dr. Catharina Meijer, drs. Sindy Plinsinga and Naghmeh Yaloui, John Scott, Kittiwan Rattanachandr, Apiyada Nonpunya, Marie Fritsch, Tania Meier, Gabor Bartucz,
drs. Pascal Meijer who pushed me to go ahead with this adventure and who pointed out the importance in the bigger Sanjeev Bhanot, Tawnya Busch, Rachelle Cali, Can Gumus, Bob Rhatigan, Michelle Franklin, Arbelia Bermudez,
picture to me. Together with the invaluable secretarial support of Ank de Bruin and Simone Lebbink we wrote history, Oumama Draoui, all in random order, and many many more.
being responsible for the creation of a new medical profile specialty.

The amazing aesthetic physicians I work with on a daily basis and are not just colleagues but have become close
friends: drs. Job Thuis for making sure I could take time off for working on science while he kept the clinic running,
dr. Pieter Siebenga, who helped me in so many ways with his knowledge of PhD projects, drs. Aleid Koppius and our
dermatologist dr. Robert van der Leest, who always showed interest in science and my PhD project, our ENT doc in
training Laura Korsten and our dermatologist in training Andreea Aaron.

The amazing international experts who inspired me, helped me and worked with me on podia around the globe
giving great shows, elegant live injection sessions and impactful presentations: Sebastian Cotofana, Nabila Azib,
Rebecca Fitzgerald, Dalvi Humzah, Sabrina Fabi, Gabriela Casabona, Tatjana Pavicic, Welf Prager, Martina Kerscher,
David Funt, Philippe Snozzi, Kate Goldie, Yana Yutskovskaya, Raj Aquilla, Arthur Swift, Joseph Hkeik, Philippe
Levi, Luiz Perez, Tim Papadopoulos, Bryan Mendelson, Niamh Corduff, Patrick Trevidic, Danny Vleggaar, Sheetal
Sapra, Cheryl Burgess, Peter Huang, Hee-Jin Kim, Yen-Yates Chao, Reha Yavuzer, Atchima Suwanchinda, Rungsima
Wanitphakdeedecha, Uliana Gout, Tingsong Lim, Gerhard and Sonia Sattler, Philip Werschler, Steve Dayan, Shino
Bay Aguilera, Wouter Peeters, Joan Vanderputte, Danilo de Gregorio, Malcolm Paul, Theodora (Dolly) Fatsea, Gilles
Delmiglio, Anver Amod, Alice Michael-Prethima, Miriam Rehbein, Pier Paolo Rovatti, Matt Stefanelli, Anushka Reddy
and many many more!

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